U.S. patent application number 13/858677 was filed with the patent office on 2013-11-21 for dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same.
This patent application is currently assigned to Laboratory Skin Care, Inc.. The applicant listed for this patent is Laboratory Skin Care, Inc.. Invention is credited to Zahra Mansouri.
Application Number | 20130309276 13/858677 |
Document ID | / |
Family ID | 43050887 |
Filed Date | 2013-11-21 |
United States Patent
Application |
20130309276 |
Kind Code |
A1 |
Mansouri; Zahra |
November 21, 2013 |
Dermal Delivery Compositions Comprising Active Agent-Calcium
Phosphate Particle Complexes and Methods of Using the Same
Abstract
Dermal delivery compositions are provided. Aspects of the dermal
delivery compositions include the presence of active agent-calcium
phosphate particle complexes, where these complexes include
uniform, rigid, spherical nanoporous calcium phosphate particles
associated with one or more active agents. Also provided are
methods of using the compositions in active agent delivery
applications.
Inventors: |
Mansouri; Zahra; (Tahoe
City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Laboratory Skin Care, Inc.; |
|
|
US |
|
|
Assignee: |
Laboratory Skin Care, Inc.
Tahoe City
CA
|
Family ID: |
43050887 |
Appl. No.: |
13/858677 |
Filed: |
April 8, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12742235 |
Apr 12, 2011 |
8445002 |
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PCT/US2010/033942 |
May 6, 2010 |
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13858677 |
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61176057 |
May 6, 2009 |
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Current U.S.
Class: |
424/400 ;
428/402 |
Current CPC
Class: |
A61P 25/06 20180101;
A61P 9/00 20180101; A61P 31/12 20180101; A61P 23/00 20180101; Y10T
428/2982 20150115; A61P 25/04 20180101; A61P 25/08 20180101; A61K
31/525 20130101; A61K 38/385 20130101; A61P 31/04 20180101; A61K
9/0014 20130101; A61K 9/10 20130101; A61K 47/6923 20170801; A61K
31/60 20130101; A61P 25/00 20180101; A61K 31/235 20130101; A61P
31/10 20180101; A61P 29/00 20180101; A61K 9/1694 20130101; A61P
33/00 20180101; A61K 47/6921 20170801; A61K 31/355 20130101; A61K
38/40 20130101; A61P 35/00 20180101; A61K 31/353 20130101; A61K
9/1611 20130101; A61K 31/355 20130101; A61K 2300/00 20130101; A61K
31/525 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/400 ;
428/402 |
International
Class: |
A61K 9/14 20060101
A61K009/14 |
Claims
1. A composition comprising uniform, rigid, spherical nanoporous
calcium phosphate calcium phosphate particles, wherein the
particles have an average particle diameter of 2 microns or less
and are complexed with an active agent.
2. The composition according to claim 1, wherein the particles have
a pore volume ranging from 30 to 85%.
3. The composition according to claim 2, wherein the particles have
a pore size ranging from 2 nm to 100 nm.
4. The composition according to claim 1, wherein the particles are
produced by: preparing a fluid composition of calcium phosphate
crystals; drying the fluid composition in a manner sufficient to
produce precursor particles; and subjecting the precursor particles
to elevated temperature and pressure in a manner sufficient to
produce uniform, rigid, spherical nanoporous calcium phosphate
calcium phosphate particles.
5. The composition according to claim 4, wherein the drying
comprises spray-drying.
6. The composition according to claim 1, wherein the composition is
a topical formulation.
7. The composition according to claim 1, wherein the amount of
active agent complexed with the particles ranges from 0.01 to 300
mg active agent per gram of particles.
8. A method of delivering an active agent to a subject, the method
comprising: applying a composition comprising: uniform, rigid,
spherical nanoporous calcium phosphate calcium phosphate particles,
wherein the particles have an average particle diameter of 2
microns or less and are complexed with an active agent; to a
topical region of the subject to deliver the active agent to the
subject.
9. The method according to claim 8, wherein the particles have a
pore volume ranging from 30 to 85%.
10. The method according to claim 9, wherein the particles have a
pore size ranging from 2 nm to 100 nm.
11. The method according to claim 8, wherein the amount of active
agent complexed with the particles ranges from 0.01 to 300 mg
active agent per gram of particles.
12. The method according to claim 8, wherein the topical location
is a mucosal location.
13. The method according to claim 8, wherein the topical location
is a keratinized skin surface.
14. The method according to claim 13, wherein the method is a
method of delivering the active agent at least into the stratum
corneum of the subject.
15. The method according to claim 13, wherein the method is a
method of delivering the active agent into the deep stratum corneum
of the subject.
16. The method according to claim 13, wherein the method is a
method of delivering the active agent through the stratum
corneum.
17. The method according to claim 13, wherein the method is a
method of delivering the active agent into the dermis of the
subject.
18. The method according to claim 13, wherein the method is a
method of systemically delivering the active agent to the subject.
Description
CROSS-REFERENCE To RELATED APPLICATIONS
[0001] Pursuant to 35 U.S.C. .sctn.119 (e), this application claims
priority to the filing date of U.S. Provisional Patent Application
Ser. No. 61/176,057 filed May 6, 2009; the disclosure of which
application is herein incorporated by reference.
INTRODUCTION
[0002] A variety of different active agents have been and continue
to be developed for use in the treatment of a variety of different
conditions, including both disease and non-disease conditions. For
such applications, an effective amount of the active agent must be
delivered to the subject in need thereof. A variety of different
delivery formulations and routes have been developed, where such
routes may vary depending on the nature of the active agent.
Typically, less invasive delivery routes are better tolerated and
therefore are more desirable.
[0003] One type of delivery route that is of great interest because
of its minimally invasive nature is dermal delivery. In dermal
delivery, an active agent composition is applied to a skin site to
deliver the active agent to the subject. Many dermal delivery
technologies currently in use or under evaluation are not entirely
satisfactory. For example, certain dermal delivery technologies may
disrupt the integrity of the stratum corneum (Sc) and/or rely on
the presence of permeation enhancers, which can cause unwanted
damage and/or irritation. In addition, certain dermal delivery
technologies may be polymer- and/or liposome based technologies,
neither of which technologies truly delivers through the Sc.
Furthermore these technologies cannot be applied to large molecular
weight bio-actives, etc.
[0004] As such, there continues to be a need for the development of
new dermal delivery technologies which overcome one or more of the
disadvantages experienced with current dermal delivery
approaches.
SUMMARY
[0005] Dermal delivery compositions are provided. Aspects of the
dermal delivery compositions include the presence of active
agent-calcium phosphate particle complexes, where these complexes
include uniform, rigid, spherical nanoporous calcium phosphate
particles associated with one or more active agents. Also provided
are methods of using the compositions in active agent delivery
applications.
BRIEF DESCRIPTION OF THE FIGURES
[0006] FIGS. 1A to 2B provide scanning electron microscope images
of uniform, rigid, spherical, nanoporous calcium phosphate
particles that find use in delivery compositions of the
invention.
[0007] FIG. 3 provides a graphical representation of the particle
size distribution of uniform, rigid, spherical, nanoporous calcium
phosphate particles that find use in delivery compositions of the
invention.
[0008] FIGS. 4A and 4B show a visual image of active agent attached
to calcium phosphate particles.
[0009] FIGS. 5A and 5B show the tape strip images following
application of a 10% calcium phospahte particle slurry to the
forearm. FIG. 5A shows calcium phosphate particle penetration to
the first layer of the stratum corneum. FIG. 5B shows calcium
phosphate particle penetration to the third layer of the stratum
corneum.
[0010] FIG. 6 is an image of mouse skin prior to application of
calcium phosphate particles. No Ca.sup.++ is evident in the upper
statum corneum.
[0011] FIG. 7A shows calcium particles in the upper stratum corneum
as well as smaller particles in the lower stratum corneum. FIG. 7B
shows the loss of integrity of the spherical calcium particles
[0012] FIG. 8 is a picture showing penetration of CTC fluorescent
throughout the stratum corneum following topical application.
[0013] FIG. 9 shows the results of STAY-C50 with and without
calcium phosphate particle tape stripping.
[0014] FIG. 10 is a table showing amount and percentage of lysozyme
with and without calcium phosphate particles as measured by tape
stripping.
[0015] FIG. 11 shows Franz cell transdermal delivery of a
riboflavin monophosphate active agent with and without calcium
phosphate particles.
DETAILED DESCRIPTION
[0016] Dermal delivery compositions are provided. Aspects of the
dermal delivery compositions include the presence of active
agent-calcium phosphate particle complexes, where these complexes
include uniform, rigid, spherical nanoporous calcium phosphate
particles associated with one or more active agents. Also provided
are methods of using the compositions in active agent delivery
applications.
[0017] Before the present invention is further described, it is to
be understood that this invention is not limited to particular
embodiments described, as such may vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to be
limiting, since the scope of the present invention will be limited
only by the appended claims.
[0018] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the invention.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges and are also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the invention.
[0019] Certain ranges are presented herein with numerical values
being preceded by the term "about." The term "about" is used herein
to provide literal support for the exact number that it precedes,
as well as a number that is near to or approximately the number
that the term precedes. In determining whether a number is near to
or approximately a specifically recited number, the near or
approximating unrecited number may be a number which, in the
context in which it is presented, provides the substantial
equivalent of the specifically recited number.
[0020] Methods recited herein may be carried out in any order of
the recited events which is logically possible, as well as the
recited order of events.
[0021] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now
described.
[0022] All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited. The publications
discussed herein are provided solely for their disclosure prior to
the filing date of the present application. Nothing herein is to be
construed as an admission that the present invention is not
entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided may be different from
the actual publication dates which may need to be independently
confirmed.
[0023] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. It is
further noted that the claims may be drafted to exclude any
optional element. As such, this statement is intended to serve as
antecedent basis for use of such exclusive terminology as "solely,"
"only" and the like in connection with the recitation of claim
elements, or use of a "negative" limitation.
[0024] In further describing various aspects of the invention, the
active agent-calcium phosphate particles according to certain
embodiments are described in greater detail, followed by a
description of embodiments of delivery compositions that include
the same, as well as methods of making and using the complexes and
delivery compositions that include the same.
Delivery Compositions
[0025] As summarized above, active agent delivery compositions are
provided. Active agent delivery compositions of the invention
include active agent-calcium phosphate particle complexes present
in a delivery vehicle. The active agent-calcium phosphate particle
complex delivery vehicle components of the delivery compositions
are now reviewed separately in greater detail.
Active Agent-Calcium Phosphate Particle Complexes
[0026] Active agent-calcium phosphate particle complexes that are
present in delivery compositions of the invention include uniform,
rigid, spherical, nanoporous calcium phosphate particles associated
with one or more active agents. As the particles are associated
with one or more active agents, one or more active agents are bound
to the particles in some manner. The active agent(s) may be bound
to the particles via a number of different associative formats,
include but not limited to: ionic binding, covalent binding, Van
der Waals interactions, hydrogen binding interactions, normal phase
and reverse phase partition interactions, etc. As such, the
particles may be described as being loaded with an amount of one or
more active agents. By "loaded" is meant that the particles include
an amount of one or more active agents (in other words an amount of
a single active agent or two or more different active agents) that
is bound to the particles. As the active agent is bound to the
particles, the active agent does not dissociate from the particles
in any substantial amount when the particles are present in the
delivery composition. Because substantially none of the active
agent dissociates from the particles, any amount that does
dissociate is 30% or less, such as 20% or less, e.g., 10% or less,
including 5% or less by weight of the originally bound amount of
active agent. The amount of active agent component (which is made
up of one or more distinct active agents) that is bound to the
particles may vary depending on the particular active agent(s)
making up the active agent bound particles, and in certain
embodiments ranges from 0.01 to 1000 mg/g, such as from 0.1 to 750
mg/g and including 1 to 300 mg/g active agent(s)/gram particle.
[0027] The active agent is reversibly associated with the calcium
phosphate particles. By "reversibly associated" is meant that the
active agent is released from the calcium phosphate particles
following delivery to a subject, e.g., following application a
delivery composition that includes the complexes to a skin site. As
reviewed in greater detail below, the calcium phosphate particles
of the complexes degrade under acidic conditions, such as under
conditions of pH 5 or less, e.g., pH 4.9 or less, pH 4.7 or less,
pH 4.5 or less, pH 4.3 or less. When the particles degrade, they
release their active agent "payload". The Stratum corneum (SC), the
outer most layer of the skin, is made up roughly 20 layers of cells
and is roughly 10 .mu.m in thickness. The pH of the SC varies
depending on its depth. Its outer most layers vary form pH 4.3 to
7.0, depending on the site sampled, or the individuals' sex. This
pH rises to around 7.0 near the Stratum granulosum (SG). This rise
is most dramatic in the last few layers of the SC adjoining the SG,
as seen below. As such, as complexes of the invention penetrate
into the SC, they degrade and concomitantly release any active
agent associated therewith.
[0028] The released active agent retains its desired activity
despite having been associated with the calcium phosphate particles
in a complex. Accordingly, binding and release of the active agent
to the calcium phosphate particles results in substantially little,
if any, damage to the active agent. As such, the activity of the
active agent is not diminished to an extent that adversely impacts
its utility, where any reduction in activity caused by the
association to the calcium phosphate particles that may occur with
a given active agent is 10% or less, such as 5% or less and
including 1% or less, e.g., as determined by an activity assay
method, e.g., as described in the Experimental Section below.
[0029] In some embodiments, association of the active agent with
the calcium phosphate particles in the complexes preserves one or
more desirable features of the active agent, such as stability. In
other words, the complex stabilizes the active agent, as compared
to a control that lacks the calcium phosphate particles.
Uniform, Rigid, Spherical, Nanoporous Calcium Phosphate
Particles
[0030] The calcium phosphate particles of the active agent-calcium
phosphate particle complexes are uniform, rigid, spherical,
nanoporous calcium phosphate particles. By "uniform" is meant that
the shape of the particles does not vary substantially, such that
the particles have substantially the same spherical shape. By
"rigid" is meant that the particles are hard, such that they are
not pliant. The term "spherical" is employed in its conventional
sense to mean a round body whose surface is at all points
substantially equidistant from the center. Of interest are calcium
phosphate particles in which the median diameter is 20 .mu.m or
less, such as 10 .mu.m or less, including 5 .mu.m or less, where in
some instances the medium diameter is 4 .mu.m or less, such as 3
.mu.m or less, including 2 .mu.m or less. In a given calcium
phosphate particulate composition, a distribution of diameters may
be present, where in some instances the majority (such as 60% or
more, 75% or more, 90% or more, 95% or more) of the particles have
diameters that range from 0.01 to 20 .mu.m, such as from 0.1 to 10
.mu.m, and including from 0.1 to 2 .mu.m. In some instances, the
proportion of the particles that have an average particle diameter
of 2 .mu.m or less is 50% or more by number, such as 70% or more by
number, including 90% or more by number.
[0031] The particles are nanoporous. By "nanoporous" is meant that
the particles have a porosity of 30% or more, such as 40% or more,
including 50% or more, where the porosity may range from 30% to
85%, such as from 40% to 70%, including from 45% to 55%, as
determined using a mercury intrusion porosimeter porosity
determination protocol as described in ASTM D 4284-88 "Standard
Test Method for Determining Pore Volume Distribution of Catalysts
by Mercury Intrusion Porosimetry". Porosity is also described by
"pore volume (ml/g)" and in such instances many range from 0.1 ml/g
to 2.0 ml/g. In some cases, the particles have a porosity such that
their internal surface area ranges from 10 m.sup.2/g to 150
m.sup.2/g, such as from 20 m.sup.2/g to 100 m.sup.2/g, including 30
m.sup.2/g to 80 m.sup.2/g, as determined using a BET gas adsorption
surface area determination protocol as described in ASTM D3663-03
Standard Test Method for Surface Area of Catalysts and Catalyst
Carriers. The pore diameter may vary, ranging in certain instances
from 2 to 100 nm, such as 5 to 80 nm, including 10 to 60 nm. In
addition, the particles may have a tapping density ranging from 0.2
g/cm.sup.3 to 0.5 g/cm.sup.3, such as from 0.25 g/cm.sup.3 to 0.45
g/cm.sup.3, including from 0.3 g/cm.sup.3 to 0.4 g/cm.sup.3. The
tap density can be measured by using standard ASTM WK13023--New
Determination of Tap Density of Metallic Powders by a Constant
Volume Measuring Method.
[0032] The particles are, in some instances, chemically pure. By
chemically pure is meant that the particles are made up of
substantially one type of calcium phosphate mineral. In some
instances, the calcium phosphate particles are described by the
molecular formula Ca.sub.10(PO.sub.4).sub.6(OH).sub.2.
[0033] In some instances, the particles are ceramic particles. By
ceramic is meant that the particles are produced using a method
which includes a step of subjecting the particles to high
temperature conditions, where such conditions are illustrated
below. High temperatures may range from 200 to 1000.degree. C.,
such as 300 to 900.degree. C. and including 300 to 800.degree. C.
In some embodiments, the particles have a compression rupture
strength ranging from 20 to 200 MPa, such as from 50 to 150 MPa,
and including 75 to 90 MPa, as determined using a SHIMADZU MCT-W500
micro-compression testing machine particle strength determination
protocol with a particle sintered at temperature of 400.degree. C.
to 900.degree. C., as described in European Patent EP1840661.
[0034] In some embodiments, the particles are biodegradable, by
which is meant that the particles degrade in some manner, e.g.,
dissolve, over time under physiological conditions. As the
particles of these embodiments are biodegradeable under
physiological conditions, they at least begin to dissolve at a
detectable rate under conditions of pH of 5 or less, such as 4.5 or
less, including 4.3 or less. As such, the particles exhibit
solubility under acidic environments of pH 5 or less, such as upon
application to the skin.
[0035] The calcium phosphate particles are non-toxic, e.g., as
determined via US-FDA 21 CFR Part 58, non-mutagenic, e.g., as
determined by Mutagenicity Ames Test, and non-irritating, e.g., as
determined via Skin Sensitization RIPT (Human).
[0036] While the uniform, rigid, spherical, nanoporous calcium
phosphate particles of the delivery compositions may vary in a
variety of different parameters, including as reviewed above, in
some embodiments the particles employed in the delivery
compositions are chemically pure particles that have a mean
diameter of 2 .mu.m.
[0037] The uniform, rigid, spherical, nanoporous calcium phosphate
particles of the delivery compositions of the invention may be
prepared using any convenient protocol. Examples of fabrication
protocols of interest include, but are not limited to, those
described in U.S. Pat. Nos. 4,781,904; 5,039,408; 5,082,566; and
5,158,756; the disclosures of which are herein incorporated by
reference. In one protocol of interest, the particles are
manufactured by spray drying a slurry that includes nano calcium
phosphate (e.g., hydroxyapatite) crystals (which may range from 2
nm to 100 nm size range) to produce uniform spherical nanoporous
calcium phosphate particles. The resultant particles are then
sintered for a period of time sufficient to provide mechanically
and chemically stable rigid spheres. In this step, the sintering
temperatures may range from 200.degree. C. to 1000.degree. C., such
as 300.degree. C. to 900.degree. C. and including 300.degree. C. to
800.degree. C. for a period of time ranging from 1 hour to 10
hours, such as 2 hours to 8 hours and including 3 hours to 6 hours.
Additional details regarding this method of manufacturing the
uniform, rigid, spherical, nanoporous calcium phosphate particles
are provided in U.S. Provisional Application Ser. No. 61/108,805,
the disclosure of which is herein incorporated by reference.
Active Agents
[0038] As summarized above, complexes of the invention include an
active agent component (made of a single type of active agent or
two or more different types of active" agents) bound to the
uniform, rigid, spherical, nanoporous calcium phosphate particles.
The term "active agent" refers to any compound or mixture of
compounds which produces a physiological result, e.g., a beneficial
or useful result, upon contact with a living organism, e.g., a
mammal, such as a human. Active agents are distinguishable from
other components of the delivery compositions, such as carriers,
diluents, lubricants, binders, colorants, etc. The active agent may
be any molecule, as well as binding portion or fragment thereof,
that is capable of modulating a biological process in a living
subject. In certain embodiments, the active agent may be a
substance used in the diagnosis, treatment, or prevention of a
disease or as a component of a medication, cosmetic or
cosmeceutical.
[0039] The active agent is a compound that interacts with or
influences or otherwise modulates a target in a living subject. The
target may be a number of different types of naturally occurring
structures, where targets of interest include both intracellular
and extra-cellular targets. The active agent may include one or
more functional groups that provide for structural interaction with
the intended target. Functional groups of interest include, but are
not limited to: groups that participate in hydrogen bonding,
hydrophobic-hydrophobic interactions, electrostatic interactions.
Specific groups of interest include, but are not limited to amines,
amides, sulfhydryls, carbonyls, hydroxyls, carboxyls, etc.
[0040] Active agents of interest may include cyclical carbon or
heterocyclic structures and/or aromatic or polyaromatic structures
substituted with one or more of the above functional groups. Also
of interest as moieties of active agents are structures found among
biomolecules, including peptides, saccharides, fatty acids,
steroids, purines, pyrimidines, derivatives, structural analogs or
combinations thereof. Such compounds may be screened to identify
those of interest, where a variety of different screening protocols
are known in the art.
[0041] The active agents may be derived from a naturally occurring
or synthetic compound that may be obtained from a wide variety of
sources, including libraries of synthetic or natural compounds. For
example, numerous means are available for random and directed
synthesis of a wide variety of organic compounds and biomolecules,
including the preparation of randomized oligonucleotides and
oligopeptides. Alternatively, libraries of natural compounds in the
form of bacterial, fungal, plant and animal extracts are available
or readily produced. Additionally, natural or synthetically
produced libraries and compounds are readily modified through
conventional chemical, physical and biochemical means, and may be
used to produce combinatorial libraries. Known pharmacological
agents may be subjected to directed or random chemical
modifications, such as acylation, alkylation, esterification,
amidification, etc. to produce structural analogs.
[0042] As such, the active agent may be obtained from a library of
naturally occurring or synthetic molecules, including a library of
compounds produced through combinatorial means, i.e., a compound
diversity combinatorial library. When obtained from such libraries,
the active agent employed will have demonstrated some desirable
activity in an appropriate screening assay for the activity.
Combinatorial libraries, as well as methods for producing and
screening such libraries, are known in the art and described in:
U.S. Pat. Nos. 5,741,713; 5,734,018; 5,731,423; 5,721,099;
5,708,153; 5,698,673; 5,688,997; 5,688,696; 5,684,711; 5,641,862;
5,639,603; 5,593,853; 5,574,656; 5,571,698; 5,565,324; 5,549,974;
5,545,568; 5,541,061; 5,525,735; 5,463,564; 5,440,016; 5,438,119;
5,223,409, the disclosures of which are herein incorporated by
reference.
[0043] Active agents of interest include small, medium and large
molecule active agents. Small molecule active agents are those
active agents having a molecular weight ranging from 18 to 2500
daltons, such as 1000 to 1500 daltons and including 250 to 1000
daltons. Medium molecule active agents are those active agents
having a molecular weight ranging from 2500 to 10,000 daltons, such
as 4,000 to 8,000 daltons and including 5000 to 7000 daltons. Large
molecule active agents are those active agents having a molecular
weight of 10,000 daltons or more, such as 100,000 daltons or more,
where in certain instances these large molecule active agents range
from 1 million to 30 million daltons, such as 5 million to 20
million daltons and including 10 million to 15 million daltons.
[0044] In certain embodiments, the active agents are present in
their salt forms, such that they carry a charge which allows them
to bind to the uniform, rigid, spherical, nanoporous calcium
phosphate particles of the delivery compositions in the desired
manner.
[0045] Active agents of interest include, but are not limited to,
those listed in Appendix A of U.S. Application Ser. No. 61/176,057;
the disclosure of which is herein incorporated by reference.
[0046] Broad categories of active agents of interest include, but
are not limited to: cardiovascular agents; pain-relief agents,
e.g., analgesics, anesthetics, anti-inflammatory agents, etc.;
nerve-acting agents; chemotherapeutic (e.g., anti-neoplastic)
agents; etc. Active agents of interest include, but are not limited
to:
[0047] antibiotics, such as: aminoglycosides, e.g. amikacin,
apramycin, arbekacin, bambermycins, butirosin, dibekacin,
dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin,
micronomcin, neomycin, netilmicin, paromycin, ribostamycin,
sisomicin, spectinomycin, streptomycin, tobramycin, trospectomycin;
amphenicols, e.g. azidamfenicol, chloramphenicol, florfenicol, and
theimaphenicol; ansamycins, e.g. rifamide, rifampin, rifamycin,
rifapentine, rifaximin; b-lactams, e.g. carbacephems, carbapenems,
cephalosporins, cehpamycins, monobactams, oxaphems, penicillins;
lincosamides, e.g. clinamycin, lincomycin; macrolides, e.g.
clarithromycin, dirthromycin, erythromycin, etc.; polypeptides,
e.g. amphomycin, bacitracin, capreomycin, etc.; tetracyclines, e.g.
apicycline, chlortetracycline, clomocycline, minocycline, etc.;
synthetic antibacterial agents, such as 2,4-diaminopyrimidines,
nitrofurans, quinolones and analogs thereof, sulfonamides,
sulfones;
[0048] antifungal agents, such as: polyenes, e.g. amphotericin B,
candicidin, dermostatin, filipin, fungichromin, hachimycin,
hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin,
perimycin; synthetic antifungals, such as allylamines, e.g.
butenafine, naftifine, terbinafine; imidazoles, e.g. bifonazole,
butoconazole, chlordantoin, chlormidazole, etc., thiocarbamates,
e.g. tolciclate, triazoles, e.g. fluconazole, itraconazole,
terconazole;
[0049] anthelmintics, such as: arecoline, aspidin, aspidinol,
dichlorophene, embelin, kosin, napthalene, niclosamide,
pelletierine, quinacrine, alantolactone, amocarzine, amoscanate,
ascaridole, bephenium, bitoscanate, carbon tetrachloride,
carvacrol, cyclobendazole, diethylcarbamazine, etc.;
[0050] antimalarials, such as: acedapsone, amodiaquin, arteether,
artemether, artemisinin, artesunate, atovaquone, bebeerine,
berberine, chirata, chlorguanide, chloroquine, chlorprogaunil,
cinchona, cinchonidine, cinchonine, cycloguanil, gentiopicrin,
halofantrine, hydroxychloroquine, mefloquine hydrochloride,
3-methylarsacetin, pamaquine, plasmocid, primaquine, pyrimethamine,
quinacrine, quinidine, quinine, quinocide, quinoline, dibasic
sodium arsenate;
[0051] antiprotozoan agents, such as: acranil, tinidazole,
ipronidazole, ethylstibamine, pentamidine, acetarsone,
aminitrozole, anisomycin, nifuratel, tinidazole, benzidazole,
suramin;
[0052] cardioprotective agents, e.g., Zinecard (dexrazoxane); blood
modifiers, including anticoagulants (e.g., coumadin (warfarin
sodium), fragmin (dalteparin sodium), heparin, innohep (tinzaparin
sodium), lovenox (enoxaparin sodium), orgaran (danaparoid sodium))
antiplatelet agents (e.g., aggrasta (tirofiban hydrochloride),
aggrenox (aspirin/extended release dipyridamole), agrylin
(anagrelide hydrochloride), ecotrin (acetylsalicylic acid), folan
(epoprostenol sodium), halfprin (enteric coated aspirin),
integrlilin (eptifibatide), persantine (dipyridamole USP), plavix
(clopidogrel bisulfate), pletal (cilostazol), reopro (abciximab),
ticlid (ticlopidine hydrochloride)), thrombolytic agents (activase
(alteplase), retavase (reteplase), streptase (streptokinase));
adrenergic blockers, such as cardura (doxazosin mesylate),
dibenzyline (phenoxybenzamine hydrochloride), hytrin (terazosin
hydrochloride), minipress (prazosin hydrochloride), minizide
(prazosin hydrochloride/polythiazide); adrenergic stimulants, such
as aldoclor (methyldopa-chlorothiazide), aldomet (methyldopa,
methyldopate HCl), aldoril (methyldopa-hydrochlorothiazide),
catapres (clonidine hydrochloride USP, clonidine), clorpres
(clonidine hydrochloride and chlorthalidone), combipres (clonidine
hydrochloride/chlorthalidone), tenex (guanfacine hydrochloride);
alpha/bet adrenergic blockers, such as coreg (carvedilol),
normodyne (labetalol hydrochloride); angiotensin converting enzyme
(ACE) inhibitors, such as accupril (quinapril hydrochloride), aceon
(perindopril erbumine), altace (ramipril), captopril, lotensin
(benazepril hydrochloride), mavik (trandolapril), monopril
(fosinopril sodium tablets), prinivil (lisinopril), univasc
(moexipril hydrochloride), vasotec (enalaprilat, enalapril
maleate), zestril (lisinopril); angiotensin converting enzyme (ACE)
inhibitors with calcium channel blockers, such as lexxel (enalapril
maleate-felodipine ER), lotrel (amlodipine and benazepril
hydrochloride), tarka (trandolapril/verapamil hydrochloride ER);
angiotensin converting enzyme (ACE) inhibitors with diuretics, such
as accuretic (quinapril HCl/hydroclorothiazide), lotensin
(benazepril hydrochloride and hydrochlorothiazide USP), prinizide
(lisinopril-hydrochlorothiazide), uniretic (moexipril
hydrochloride/hydrochlorothiazide), vaseretic (enalapril
maleate-hydrochlorothiazide), zestoretic (lisinopril and
hydrochlorothiazide); angiotensin II receptor antagonists, such as
atacand (candesartan cilexetil), avapro (irbesartan), cozaar
(losartan potassium), diovan (valsartan), micardis (telmisartan),
teveten (eprosartan mesylate); angiotensin II receptor antagonists
with diuretics, such as avalide (irbesartan-hydrochlorothiazide),
diovan (valsartan and hydrochlorothiazide), hyzaar (losartan
potassium-hydrochlorothiazide); antiarrhythmics, such as Group I
(e.g., mexitil (mexiletine hydrochloride, USP), norpace
(disopyramide phosphate), procanbid (procainamide hydrochloride),
quinaglute (quinidine gluconate), quinidex (quinidine sulfate),
quinidine (quinidine gluconate injection, USP), rythmol
(propafenone hydrochloride), tambocor (flecainide acetate),
tonocard (tocainide HCl)), Group II (e.g., betapace (sotalol HCl),
brevibloc (esmolol hydrochloride), inderal (propranolol
hydrochloride), sectral (acebutolol hydrochloride)), Group III
(e.g., betapace (sotalol HCl), cordarone (amiodarone
hydrochloride), corvert (ibutilide fumarate injection), pacerone
(amiodarone HCl), tikosyn (dofetilide)), Group IV (e.g., calan
(verapamil hydrochloride), cardizem (diltiazem HCl), as well as
adenocard (adenosine), lanoxicaps (digoxin), lanoxin (digoxin));
antilipemic acids, including bile acid sequestrants (e.g., colestid
(micronized colestipol hydrochloride), welchol (colesevelam
hydrochloride)), fibric acid derivatives (e.g., atromid
(clofibrate), lopid (gemfibrozal tablets, USP), tricor (fenofibrate
capsules)), HMG-CoA reductase inhibitors (e.g., baycol
(cerivastatin sodium tablets), lescol (fluvastatin sodium), lipitor
(atorvastatin calcium), mevacor (lovastatin), pravachol
(pravastatin sodium), zocor (simvastatin)), Nicotinic Acid (e.g.,
Niaspan (niacin extended release tablets)); beta adrenergic
blocking agents, e.g., betapace (sotalol HCl), blocadren (timolol
maleate), brevibloc (esmolol hydrochloride), cartrol (carteolol
hydrochloride), inderal (propranolol hydrochloride), kerlone
(betaxolol hydrochloride), nadolol, sectral (acebutolol
hydrochloride), tenormin (atenolol), toprol (metoprolol succinate),
zebeta (bisoprolol fumarate); beta adrenergic blocking agents with
diuretics, e.g., corzide (nadolol and bendroflumethiazide tablets),
inderide (propranolol hydrochloride and hydroclorothiazide),
tenoretic (atenolol and chlorthalidone), timolide (timolol
maleate-hydrochlorothiazide), ziac (bisoprolol fumarate and
hydrochloro-thiazide); calcium channel blockers, e.g., adalat
(nifedipine), calan (verapamil hydrochloride), cardene (nicardipine
hydrochloride), cardizem (diltiazem HCl), covera (verapamil
hydrochloride), isoptin (verapamil hydrochloride), nimotop
(nimodipine), norvasc (amlodipine besylate), plendil (felodipine),
procardia (nifedipine), sular (nisoldipine), tiazac (diltiazem
hydrochloride), vascor (bepridil hydrochloride), verelan (verapamil
hydrochloride); diuretics, including carbonic anhydrase inhibitors
(e.g., daranide (dichlorphenamide)), combination diuretics (e.g.,
aldactazide (spironolactone with hydrochlorothiazide), dyazide
(triamterene and hydrochlorothiazide), maxzide (triamterene and
hydrochlorothiazide), moduretic (amiloride
HCl-hydrochlorothiazide)), loop diuretics (demadex (torsemide),
edecrin (ethacrynic acid, ethacrynate sodium), furosemide),
potassium-sparing diuretics (aldactone (spironolactone), dyrenium
(triamterene), midamor (amiloride HCl)), thiazides & related
diuretics (e.g., diucardin (hydroflumethiazide), diuril
(chlorothiazide, chlorothiazide sodium), enduron
(methyclothiazide), hydrodiuril hydrochlorothiazide), indapamide,
microzide. (hydrochlorothiazide) mykrox (metolazone tablets),
renese (polythi-azide), thalitone (chlorthalidone, USP), zaroxolyn
(metolazone)); inotropic agents, e.g., digitek (digoxin), dobutrex
(dobutamine), lanoxicaps (digoxin), lanoxin (digoxin), primacor
(milrinone lactate); activase (alteplase recombinant); adrenaline
chloride (epinephrine injection, USP); demser (metyrosine),
inversine (mecamylamine HCl), reopro (abciximab), retavase
(reteplase), streptase (streptokinase), tnkase (tenecteplase);
vasodilators, including coronary vasodilators (e.g., imdur
(isosorbide mononitrate), ismo (isosorbide mononitrate), isordil
(isosorbide dinitrate), nitrodur (nitroglycerin), nitrolingual
(nitroglycerin lingual spray), nitrostat (nitroglycerin tablets,
USP), sorbitrate (isosorbide dinitrate)), peripheral vasodilators
& combinations (e.g., corlopam (fenoldopam mesylate), fiolan
(epoprostenol sodium), primacor (milrinone lactate)), vasopressors,
e.g., aramine (metaraminol bitartrate), epipen (EpiPen 0.3 mg brand
of epinephrine auto injector, EpiPen Jr. 0.15 mg brand of
epinephrine auto injector), proamatine (midodrine hydrochloride);
etc.
[0053] psychopharmacological agents, such as (1) central nervous
system depressants, e.g. general anesthetics (barbiturates,
benzodiazepines, steroids, cyclohexanone derivatives, and
miscellaneous agents), sedative-hypnotics (benzodiazepines,
barbiturates, piperidinediones and triones, quinazoline
derivatives, carbamates, aldehydes and derivatives, amides, acyclic
ureides, benzazepines and related drugs, phenothiazines, etc.),
central voluntary muscle tone modifying drugs (anticonvulsants,
such as hydantoins, barbiturates, oxazolidinediones, succinimides,
acylureides, glutarimides, benzodiazepines, secondary and tertiary
alcohols, dibenzazepine derivatives, valproic acid and derivatives,
GABA analogs, etc.), analgesics (morphine and derivatives,
oripavine derivatives, morphinan derivatives, phenylpiperidines,
2,6-methane-3-benzazocaine derivatives, diphenylpropylamines and
isosteres, salicylates, p-aminophenol derivatives, 5-pyrazolone
derivatives, arylacetic acid derivatives, fenamates and isosteres,
etc.) and antiemetics (anticholinergics, antihistamines,
antidopaminergics, etc.), (2) central nervous system stimulants,
e.g. analeptics (respiratory stimulants, convulsant stimulants,
psychomotor stimulants), narcotic antagonists (morphine
derivatives, oripavine derivatives, 2,6-methane-3-benzoxacine
derivatives, morphinan derivatives) nootropics, (3)
psychopharmacologicals, e.g. anxiolytic sedatives (benzodiazepines,
propanediol carbamates) antipsychotics (phenothiazine derivatives,
thioxanthine derivatives, other tricyclic compounds, butyrophenone
derivatives and isosteres, diphenylbutylamine derivatives,
substituted benzamides, arylpiperazine derivatives, indole
derivatives, etc.), antidepressants (tricyclic compounds, MAO
inhibitors, etc.), (4) respiratory tract drugs, e.g. central
antitussives (opium alkaloids and their derivatives);
[0054] pharmacodynamic agents, such as (1) peripheral nervous
system drugs, e.g. local anesthetics (ester derivatives, amide
derivatives), (2) drugs acting at synaptic or neuroeffector
junctional sites, e.g. cholinergic agents, cholinergic blocking
agents, neuromuscular blocking agents, adrenergic agents,
antiadrenergic agents, (3) smooth muscle active drugs, e.g.
spasmolytics (anticholinergics, musculotropic spasmolytics),
vasodilators, smooth muscle stimulants, (4) histamines and
antihistamines, e.g. histamine and derivative thereof (betazole),
antihistamines (H1-antagonists, H2-antagonists), histamine
metabolism drugs, (5) cardiovascular drugs, e.g. cardiotonics
(plant extracts, butenolides, pentadienolids, alkaloids from
erythrophleum species, ionophores, -adrenoceptor stimulants, etc),
antiarrhythmic drugs, antihypertensive agents, antilipidemic agents
(clofibric acid derivatives, nicotinic acid derivatives, hormones
and analogs, antibiotics, salicylic acid and derivatives),
antivaricose drugs, hemostyptics, (6) blood and hemopoietic system
drugs, e.g. antianemia drugs, blood coagulation drugs (hemostatics,
anticoagulants, antithrombotics, thrombolytics, blood proteins and
their fractions), (7) gastrointestinal tract drugs, e.g. digestants
(stomachics, choleretics), antiulcer drugs, antidiarrheal agents,
(8) locally acting drugs;
[0055] chemotherapeutic agents, such as (1) anti-infective agents,
e.g. ectoparasiticides (chlorinated hydrocarbons, pyrethins,
sulfurated compounds), anthelmintics, antiprotozoal agents,
antimalarial agents, antiamebic agents, antileiscmanial drugs,
antitrichomonal agents, antitrypanosomal agents, sulfonamides,
antimycobacterial drugs, antiviral chemotherapeutics, etc., and (2)
cytostatics, i.e. antineoplastic agents or cytotoxic drugs, such as
alkylating agents, e.g. Mechlorethamine hydrochloride (Nitrogen
Mustard, Mustargen, HN2), Cyclophosphamide (Cytovan, Endoxana),
Ifosfamide (IFEX), Chlorambucil (Leukeran), Melphalan
(Phenylalanine Mustard, L-sarcolysin, Alkeran, L-PAM), Busulfan
(Myleran), Thiotepa (Triethylenethiophosphoramide), Carmustine
(BiCNU, BCNU), Lomustine (CeeNU, CCNU), Streptozocin (Zanosar) and
the like; plant alkaloids, e.g. Vincristine (Oncovin), Vinblastine
(Velban, Velbe), Paclitaxel (Taxol), and the like; antimetabolites,
e.g. Methotrexate (MTX), Mercaptopurine (Purinethol, 6-MP),
Thioguanine (6-TG), Fluorouracil (5-FU), Cytarabine (Cytosar-U,
Ara-C), Azacitidine (Mylosar, 5-AZA) and the like; antibiotics,
e.g. Dactinomycin (Actinomycin D, Cosmegen), Doxorubicin
(Adriamycin), Daunorubicin (duanomycin, Cerubidine), Idarubicin
(Idamycin), Bleomycin (Blenoxane), Picamycin (Mithramycin,
Mithracin), Mitomycin (Mutamycin) and the like, and other
anticellular proliferative agents, e.g. Hydroxyurea (Hydrea),
Procarbazine (Mutalane), Dacarbazine (DTIC-Dome), Cisplatin
(Platinol) Carboplatin (Paraplatin), Asparaginase (Elspar)
Etoposide (VePesid, VP-16-213), Amsarcrine (AMSA, m-AMSA), Mitotane
(Lysodren), Mitoxantrone (Novatrone), and the like.
[0056] Drug compounds of interest are also listed in: Goodman &
Gilman's, The Pharmacological Basis of Therapeutics (9th Ed)
(Goodman et al. eds) (McGraw-Hill) (1996); and 2001 Physician's
Desk Reference.
[0057] Specific categories and examples of active agents include,
but are not limited to: those appearing the following table:
TABLE-US-00001 Therapeutic Pharmacological Category Class
Structural Examples (Does not include derivatives) Analgesics
Opioid Analgesics Includes drugs such as Morphine, Meperidine and
Propoxyphene Non-opioid Includes drugs such as Sodium Salicylate,
Diflunisal, Para-Aminophenol Analgesics Derivatives, Anthranilic
Acid Derivatives, and Phenylpropionic Acid Derivatives Anesthetics
Antibacterials Beta-lactam, Cephalosporins Beta-lactam, Penicillins
Beta-lactam, Other Includes drugs such as Loracarbef Macrolides
Quinolones Sulfonamides Tetracyclines Antibacterials, Other
Includes drugs such as Trimethoprim, Vancomycin, Lincomycin,
Clindamycin, Furazolidone, Nitrofurantoin, Linezolid, Bacitracin,
Chloramphenicol, Daptomycin, Fosfomycin, Methenamine,
Metronidazole, Mupirocin, Rifaximin, Spectinomycin Anticonvulsants
Calcium Channel Includes drugs such as Nifedipine Modifying Agents
Gamma-aminobutyric Includes drugs such as Clonazepam, Diazepam, and
Phenobarbital Acid (GABA) Augmenting Agents Glutamate Reducing
Agents Sodium Channel Inhibitors Antidementia Cholinesterase Agents
Inhibitors Glutamate Pathway Modifiers Antidementia Agents,
Includes drugs such as Ergoloid Mesylates Other Antidepressants
Monoamino Oxidase (Type A) Inhibitors Reuptake Inhibitors
Antidepressants, Includes drugs such as Bupropion, Maprotiline,
Mirtazapine, Trazodone Other Antiemetics Antifungals Includes drugs
such as Amphotericin B, and Ketoconazole Antigout Agents Anti-
Glucocorticoids See Adrenal Pharmacologic Class for similar/related
therapies inflammatories Nonsteroidal Anti- See Non-opioid
Analgesics Pharmacologic Class for similar/related therapies
inflammatory Drugs (NSAIDs) Antimigraine Abortive See Analgesics
Therapeutic Category for similar/related therapies Agents
Prophylactic See Autonomic Agents and Cardiovascular Agents
Therapeutic Categories for similar/related therapies
Antimycobacterials Antituberculars Includes drugs such as
Isoniazid, Pyridoxine and Cycloserine Antimycobacterials, Includes
drugs such as Clofazimine, Dapsone, Rifabutin Other Antineoplastics
Alkylating Agents Includes drugs such as Chlorambucil, Thiotepa,
Busulfan, Dacarbazine, and Carmustine Antimetabolites Includes
drugs such as Methotrexate, Cytarabine, and Mercaptopurine Immune
Modulators Includes biotech drugs as various Monoclonal Antibodies,
Cytokines, and Vaccines Interferones and Interleukins Molecular
Target Includes drugs such as Vaccines, Antisense and Gene
Therapies Inhibitors Nucleoside Analogues Includes drugs such as
dIdC, and AZT Protective Agents Includes biotech drugs as Vaccines
Topoisomerase Inhibitors Antineoplastics, Includes drugs such as
Carboplatin, Cisplatin, Oxaliplatin Other Antiparasitics
Anthelmintics Includes drugs such as Mebendazole, Pyrantel Pamoate,
Bithionol, and Paromomycin Antiprotozoals Includes drugs such as
Chloroquine, Pyrimethamine, Metronidazole, Furazolidone,
Melarsoprol, Suramin and Tetracyclines Pediculicides/Scabicides
Includes drugs such as Crotamiton, Lindane, Benzyl Benzoate and
Sulfur Antiparkinson Catechol O- Agents methyltransferase (COMT)
Inhibitors Dopamine Agonists Includes drugs such as Levodopa, and
Deprenyl Antiparkinson Includes drugs such as Benztropine,
Biperidin, Bromocriptine, Agents, Other Diphenhydramine,
Procyclidine, Selegiline, Trihexyphenidyl Antipsychotics
Non-phenothiazines Includes drugs such as Chlorprothixene, and
Thiothixene Non- Includes drugs such as Haloperidol, Molindone, and
Loxapine phenothiazines/ Atypicals Phenothiazines Includes drugs
such as Fluphenazine Antivirals Anti-cytomegalovirus Includes
biotech drugs as Vaccines (CMV) Agents Antiherpetic Agents Includes
biotech drugs as Vaccines and Recombinant Proteins Anti-human
immunodeficiency virus (HIV) Agents, Fusion Inhibitors Anti-HIV
Agents, Non-nucleoside Reverse Transcriptase Inhibitors Anti-HIV
Agents, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
Anti-HIV Agents, Protease Inhibitors Anti-influenza Agents Includes
biotech drugs such as Vaccines, Flumist, and Thymidine Kinase
Inhibitors Antivirals, Other Includes drugs such as Adefovir and
Ribavirin Anxiolytics Antidepressants Anxiolytics, Other Includes
drugs such as Buspirone and Meprobamate Autonomic
Parasympatholytics Agents Parasympathomimetics Sympatholytics See
Cardiovascular Agents and Genitourinary Agents Therapeutic
Categories for similar/related therapies Sympathomimetics See
Cardiovascular Agents Therapeutic Category for similar/related
therapies Bipolar Agents Blood Glucose Antihypoglycemics Regulators
Hypoglycemics, Oral Insulins Blood Anticoagulants Includes drugs
such as Acetaminophen, Coumarin Derivatives, Aspirin,
Products/Modifiers/ Heparin, and Indandione Derivatives Volume
Expanders Blood Formation Products Coagulants Platelet Aggregation
Inhibitors Cardiovascular Alpha-adrenergic See Autonomic Agents
Therapeutic Category for similar/related therapies Agents Agonists
Alpha-adrenergic Includes drugs such as Phenolamine Mesylate, and
Prazosin HCl Blocking Agents Antiarrhythmics Includes drugs such as
Bretylium, Digitalis, Quinidine, and Atropine Beta-adrenergic
Includes drugs such as Atenolol and related compounds Blocking
Agents Calcium Channel Includes drugs such as Nifedipine Blocking
Agents Direct Cardiac Inotropics Diuretics Includes drugs such as
Furosemide, and Spironolactone Dyslipidemics Renin-angiotensin-
Includes drugs such as Captopril, and Saralasin Acetate aldosterone
System Inhibitors Vasodilators Includes drugs such as Sodium
Nitroprusside, Nitroglycerine Central Amphetamines Nervous System
Agents Non-amphetamines Dental and Includes such drugs as CHG Oral
Agents Dermatological Dermatological Includes drugs such as
Lidocaine, Dibucaine, and Diperodon Agents Anesthetics
Dermatological Includes drugs such as Bacitracin,
Chlorotetracycline, and Erythromycin Antibacterials Dermatological
Includes drugs such as Haloprogin, Tolnaftate, Imidazoles, and
Polyene Antifungals Antibiotics Dermatological Anti- Includes drugs
such as Hydrocortisone, Amcinonide, and Desonide inflammatories
Dermatological Includes drugs such as Benzocaine, Lidocaine,
Pramoxine, Diphenhydramine, Antipruritic Agents and Hydrocortisone
Dermatological HIV-Inhibitors of reverse transcriptase (Nucleoside
analogs, Non-nucleoside Antivirals analogs, and Nucleotide
analogs), Viral packaging inhibitors (Protease Inhibitors), Fusion
Inhibitors, Herpes Virus-Nucleoside analogs (Acyclovir,
Valacyclovir, Famciclovir and Penciclovir), Interferone Alpha, and
Imiquimod Dermatological Includes drugs such as Urea, and Salicylic
Acid Keratolytics Dermatological Includes drugs such as
Vinblastine, and Vincristine Mitotic Inhibitors Dermatological
Includes drugs such as Hydroquinone and Trioxsalen
Photochemotherapy Agents Dermatological Includes drugs such as
Tretinoin Retinoids Dermatological Tar Includes drugs such as
Anthraquinone derivatives (Anthralin) Derivatives Dermatological
Includes drugs such as Calcitriol, and Calcipotriol Vitamin D
Analogs Dermatological Includes drugs such as Collagenase,
Sutilains and Dextranomers Wound Care Agents Dermatological
Includes drugs such as Benzoyl Peroxide, and Salicylic Acid
Antiacne Dermatological Includes actives such as
3_Benzylidene_Camphors, 2-phenylbenzimidazole- UVA/UVB Block
5-sulfonic acid, Octyl Salicylate, Homosalate, Octylmethyl PABA, ,
Octyl Methoxycinnamate, Octocrylene, Oxybenzone, Menthyl
Anthranilate, Titanium Dioxide, Zinc Oxide, Avobenzone Deterrents/
Alcohol Deterrents Replacements Enzyme Replacements/ Modifiers
Gastrointestinal Antispasmodics, Agents Gastrointestinal Histamine2
(H2) Includes drugs such as Cimetidine, and Ranitidine Blocking
Agents Irritable Bowel Syndrome Agents Protectants Proton Pump
Inhibitors Gastrointestinal Includes drugs such as Sevelamer,
Ursodiol, Antisense, Vaccines and Mab Agents, Other and their
fragments Genitourinary Antispasmodics, Agents Urinary Benign
Prostatic See Autonomic Agents and Cardiovascular Agents
Therapeutic Categories for Hypertrophy Agents similar/related
therapies Impotence Agents Prostaglandins See Hormonal Agents,
Stimulant/Replacement/Modifying TherapeuticCategory for
similar/related therapies
Hormonal Adrenal See Anti-inflammatories Therapeutic Category for
similar/related therapies Agents, Stimulant/ Replacement/ Modifying
Parathyroid/Metabolic Bone Disease Agents Pituitary Prostaglandins
See Genitourinary Agents Therapeutic Category for similar/related
therapies Sex Hormones/Modifiers Thyroid Includes drugs such as
Levothyroxine Sodium, and Methimazoie Hormonal Adrenal Agents,
Suppressant Pituitary Includes biotech drugs as hGH Sex Includes
biotech drugs as Estradiol Hormones/Modifiers Thyroid Immunological
Immune Stimulants Includes biotech drugs as various Monoclonal
Antibodies, Interferones and Agents Interleukins Immune Includes
biotech drugs as various Monoclonal Antibodies, Interferones and
Suppressants Interleukins Immunomodulators Includes biotech drugs
as various Monoclonal Antibodies, Interferones and Interleukins
Inflammatory Glucocorticoids See Hormonal Agents,
Stimulant/Replacement/Modifying Therapeutic Bowel Disease Category
for similar/related therapies Agents Salicylates Sulfonamides See
Antibacterial Therapeutic Category for similar/related therapies
Ophthalmic Ophthalmic Anti- Includes drugs such as Cromolyn Agents
allergy Agents Ophthalmic Includes drugs such as Bacitracin,
Chloramphenicol, Erythromycin, and Antibacterials Polymyxin B
Sulfate Ophthalmic Includes drugs such as Amphotericm B,
Miconazole, Natamycin and Nystatin Antifungals Ophthalmic Includes
drugs such as Pilocarpine HCl, Carbachol, Physostigmine Salicylate,
Antiglaucoma Agents Isoflurophate, and Acetazolamide Ophthalmic
Anti- Includes drugs such as Hydrocortisone, Dexamethasone, and
Medrysone inflammatories Ophthalmic Antivirals Includes drugs such
as Idoxuridine, Trifluridine, Antisense, and Vidarabine
Ophthalmics, Other Includes drugs such as Formivirsen Otic Agents
Otic Antibacterials Includes drugs such as Chloramphenicol,
Neomycin Sulfate, and Polymyxins Otic Anti- inflammatories
Respiratory Antihistamines Tract Agents Antileukotrienes
Bronchodilators, Anticholinergic Bronchodilators, Anti- Includes
drugs such as Corticosteroid derivatives inflammatories
Bronchodilators, Phosphodiesterase 2 Inhibitors (Xanthines)
Bronchodilators, Includes drugs such as Albuterol, Terbutaline, and
Isoproterenol Sympathomimetic Mast Cell Stabilizers Includes drugs
such as Cromolyn Sodium Mucolytics Respiratory Tract Includes drugs
such as Alpha-1-proteinase Inhibitor, Human; Benzonatate; Agents,
Other Guaifenesin; Iodinated Glycerol; Potassium Iodide;
Tetrahydrozoline Sedatives/ Hypnotics Skeletal Muscle Includes
drugs such as Carisoprodol, Chlorphenesin Carbamate, Relaxants
Chlorzoxazone, and Cyclobenzaprine HCl Therapeutic
Electrolytes/Minerals Nutrients/ Minerals/Electrolytes Vitamins
Toxicologic Opioid Antagonists Agents Erectial Tadalafil,
sildenafil, vardenafil dysfunction Agents
[0058] Specific compounds of interest also include, but are not
limited to:
TABLE-US-00002 Hydrocodone/Acetaminophen Lipitor Azithromycin
Nexium Simvastatin Advair Diskus Oxycodone ER Prevacid Sertraline
Plavix Fentanyl Transdermal Singulair Amlodipine Besylate Seroquel
Fexofenadine Effexor XR Amoxicillin/Pot Clav Lexapro Omeprazole
Actos Gabapentin Protonix Fluticasone Nasal Vytorin Lisinopril
Topamax Oxycodone w/Acetaminophen Risperdal Metoprolol Succinate
Abilify Metformin Cymbalta NovoLog Lamictal Amlodipine Besylate
Zyprexa Levothyroxine Levaquin Zolpidem Tartrate Celebrex
Amoxicillin Zetia Ondansetron Valtrex Paroxetine Crestor Alprazolam
Fosamax Lovastatin Zyrtec Albuterol Aerosol Lantus Fluoxetine
Adderall XR Lorazepam Diovan Warfarin Avandia Pravastatin Tricor
Cefdinir Aciphex Atenolol Diovan HCT Hydrochlorothiazide OxyContin
Tramadol Concerta Clonazepam Coreg Cephalexin Flomax Bupropion SR
Lyrica Oxycodone Wellbutrin XL Propoxyphene-N/Acetaminophen Aricept
Lisinopril/Hydrochlorothiazide Imitrex Oral Finasteride Ambien
Citalopram HBr Lotrel Nifedipine ER Nasonex Cyclobenzaprine Toprol
XL Furosemide Oral Ambien CR Carisoprodol Enbrel Morphine Sulfate
ER Spiriva Ciprofloxacin HCl Viagra Metoprolol Tartrate Lidoderm
Prednisone Oral Actonel Cartia XT Chantix Amphetamine Salt Cmb
Norvasc Clindamycin Systemic Lovenox Nabumetone Provigil Potassium
Chloride Lunesta Ondansetron ODT Altace Diltiazem CD Keppra
Verapamil SR Geodon Oral Albuterol Nebulizer Solution Cozaar
Felodipine ER Detrol LA Quinapril Atripla Clopidogrel Truvada
Ibuprofen CellCept Ranitidine HCl Pulmicort Respules
Glyburide/Metformin HCl Humalog Minocycline Depakote ER Triamterene
w/Hydrochlorothiazide Depakote Enalapril Premarin Tabs Oxybutynin
Chl ER Synthroid Tramadol HCl/Acetaminophen Niaspan Meloxicam
Byetta Acetaminophen w/Codeine Budeprion XL Spironolactone
Strattera Hydroxyzine Combivent Naproxen Trileptal Glipizide ER
Yasmin 28 Trazodone HCl Flovent HFA Fluconazole Skelaxin
Mirtazapine Prograf Promethazine Tabs Arimidex Phentermine Evista
Glyburide Hyzaar Tizanidine HCl Namenda Diazepam Januvia
Venlafaxine Humira Metformin HCl ER Cialis Buspirone HCl Reyataz
Diclofenac Sodium Xalatan Doxycycline Omnicef Gemfibrozil Avelox
Cefprozil ProAir HFA Propranolol HCl Asacol Phenytoin Sodium Ext
Benicar HCT Isosorbide Mononitrate Fentanyl Oral Citra
Clarithromycin Requip Clozapine Boniva Vancocin HCl Caduet
Glimepiride Avapro Clotrimazole/Betamethasone Gleevec
Carbidopa/Levodopa Kaletra Mupirocin Ortho TriCyclen Lo
Desmopressin Acetate Benicar Nitrofurantoin Monohydrate AndroGel
Clonidine Xopenex Clarithromycin ER Procrit Trimethoprim Sulfate
Lamisil Oral Nifedical XL Avalide Carvedilol Nasacort AQ
Methotrexate Combivir Hydrocodone/Ibuprofen Allegra-D 12 Hour
Methylprednisolone Tabs Duragesic Etodolac Copaxone Nifedipine
RenaGel Bupropion ER Femara Nystatin Systemic Enbrel Sureclick
Benazepril NovoLog Mix 70/30 Zegerid Clarinex Cefuroxime Axetil
Aldara Amitriptyline Forteo Bupropion XL Suboxone Clobetasol
Avodart Acyclovir Paxil CR Benzonatate Norvir Allopurinol Avandamet
Penicillin VK Restasis Temazepam Avonex Baclofen Sensipar Tretinoin
Tarceva Sulfamethoxazole/Tri Patanol Terbinafine HCL Yaz Methadone
HCl Non-Injection Lovaza Amiodarone Mirapex Ketoconazole Topical
Focalin XR Hydroxy-chloroquine Cosopt Nitrofurantoin Macrocrystals
Zyvox Triamcinolone Acetonide Top Epzicom Lithium Carbonate
NuvaRing Terazosin Actiq Itraconazole Foxamax Plus D Hydralazine
Actoplus Met Butalbital/Acetaminophen/Caffeine Lumigan Labetalol
Rhinocort Aqua Fosinopril Sodium Solodyn Cilostazol Thalomid
Mometasone Topical Fuzeon Doxazosin Astelin Clindamycin Topical
BenzaClin Metoclopramide Relpax Medroxyprogesterone Injection
Viread Megestrol Oral Suspension Casodex Folic Acid Vigamox
Zostavax Vesicare Nitroglycerin Humalog Mix 75/25 Pn
Bisoprolol/Hydrochlorothiazide Trizivir Polyethylene Glycol
Budeprion SR Prednisolone Sd Phosphate Oral Xeloda Azathioprine
Sustiva Calcitriol Levitra Torsemide Endocet Glipizide Risperdal
Consta Sotalol Aggrenox Zonisamide Humira Pen Hydromorphone HCl
Kadian Potassium Chloride Differin Oxcarbazepine Catapres-TTS
Diltiazem SR Alphagan P Albuterol Sulfate/Ipratropium Tussionex
Metronidazole Tabs Zyrtec Syrup Cabergoline Maxalt Cyclosporine
Zoloft Estradiol Oral Prilosec Methocarbamol Ciprodex Otic
Tamoxifen Temodar Promethazine/Codeine TobraDex Ursodiol Zyrtec-D
Mercaptopurine Welchol Ribavirin Maxalt MLT Famotidine Asmanex
PhosLo Atacand Indomethacin SR Coumadin Tabs Lamotrigine Dovonex
Cefadroxil Klor-Con Ipratropium Br Nebulizer Solution Pegasys
Fluvoxamine Ultram ER Methylphenidate Betaseron Metolazone Zovirax
Topical Microgestin Fe 1/20 Trinessa Dexamphetamine Sulfate
Pulmozyme Diltiazem ER Neupogen Clindesse Humulin N Flecainide
Acetate Micardis HCT Metronidazole Top Ortho Evra Microgestin Fe
1/20 Allegra-D 12 Hours Evoclin Fentora Primidone Enablex
Fluocinonide Famvir Terconazole Avinza Carbidopa/Levodopa ER
Prempro Leflunomide Coreg CR Midodrine HCl Marinol
[0059] Specific compounds of interest also include, but are not
limited to:
[0060] antineoplastic agents, as disclosed in U.S. Pat. Nos.
5,880,161, 5,877,206, 5,786,344, 5,760,041, 5,753,668, 5,698,529,
5,684,004, 5,665,715, 5,654,484, 5,624,924, 5,618,813, 5,610,292,
5,597,831, 5,530,026, 5,525,633, 5,525,606, 5,512,678, 5,508,277,
5,463,181, 5,409,893, 5,358,952, 5,318,965, 5,223,503, 5,214,068,
5,196,424, 5,109,024, 5,106,996, 5,101,072, 5,077,404, 5,071,848,
5,066,493, 5,019,390, 4,996,229, 4,996,206, 4,970,318, 4,968,800,
4,962,114, 4,927,828, 4,892,887, 4,889,859, 4,886,790, 4,882,334,
4,882,333, 4,871,746, 4,863,955, 4,849,563, 4,845,216, 4,833,145,
4,824,955, 4,785,085, 476,925, 4,684,747, 4,618,685, 4,611,066,
4,550,187, 4,550,186, 4,544,501, 4,541,956, 4,532,327, 4,490,540,
4,399,283, 4,391,982, 4,383,994, 4,294,763, 4,283,394, 4,246,411,
4,214,089, 4,150,231, 4,147,798, 4,056,673, 4,029,661,
4,012,448;
[0061] psycopharmacological/psychotropic agents, as disclosed in
U.S. Pat. Nos. 5,192,799, 5,036,070, 4,778,800, 4,753,951,
4,590,180, 4,690,930, 4,645,773, 4,427,694, 4,424,202, 4,440,781,
5,686,482, 5,478,828, 5,461,062, 5,387,593, 5,387,586, 5,256,664,
5,192,799, 5,120,733, 5,036,070, 4,977,167, 4,904,663, 4,788,188,
4,778,800, 4,753,951, 4,690,930, 4,645,773, 4,631,285, 4,617,314,
4,613,600, 4,590,180, 4,560,684, 4,548,938, 4,529,727, 4,459,306,
4,443,451, 4,440,781, 4,427,694, 4,424,202, 4,397,853, 4,358,451,
4,324,787, 4,314,081, 4,313,896, 4,294,828, 4,277,476, 4,267,328,
4,264,499, 4,231,930, 4,194,009, 4,188,388, 4,148,796, 4,128,717,
4,062,858, 4,031,226, 4,020,072, 4,018,895, 4,018,779, 4,013,672,
3,994,898, 3,968,125, 3,939,152, 3,928,356, 3,880,834,
3,668,210;
[0062] cardiovascular agents, as disclosed in U.S. Pat. Nos.
4,966,967, 5,661,129, 5,552,411, 5,332,737, 5,389,675, 5,198,449,
5,079,247, 4,966,967, 4,874,760, 4,954,526, 5,051,423, 4,888,335,
4,853,391, 4,906,634, 4,775,757, 4,727,072, 4,542,160, 4,522,949,
4,524,151, 4,525,479, 4,474,804, 4,520,026, 4,520,026, 5,869,478,
5,859,239, 5,837,702, 5,807,889, 5,731,322, 5,726,171, 5,723,457,
5,705,523, 5,696,111, 5,691,332, 5,679,672, 5,661,129, 5,654,294,
5,646,276, 5,637,586, 5,631,251, 5,612,370, 5,612,323, 5,574,037,
5,563,170, 5,552,411, 5,552,397, 5,547,966, 5,482,925, 5,457,118,
5,414,017, 5,414,013, 5,401,758, 5,393,771, 5,362,902, 5,332,737,
5,310,731, 5,260,444, 5,223,516, 5,217,958, 5,208,245, 5,202,330,
5,198,449, 5,189,036, 5,185,362, 5,140,031, 5,128,349, 5,116,861,
5,079,247, 5,070,099, 5,061,813, 5,055,466, 5,051,423, 5,036,065,
5,026,712, 5,011,931, 5,006,542, 4,981,843, 4,977,144, 4,971,984,
4,966,967, 4,959,383, 4,954,526, 4,952,692, 4,939,137, 4,906,634,
4,889,866, 4,888,335, 4,883,872, 4,883,811, 4,847,379, 4,835,157,
4,824,831, 4,780,538, 4,775,757, 4,774,239, 4,771,047, 4,769,371,
4,767,756, 4,762,837, 4,753,946, 4,752,616, 4,749,715, 4,738,978,
4,735,962, 4,734,426, 4,734,425, 4,734,424, 4,730,052, 4,727,072,
4,721,796, 4,707,550, 4,704,382, 4,703,120, 4,681,970, 4,681,882,
4,670,560, 4,670,453, 4,668,787, 4,663,337, 4,663,336, 4,661,506,
4,656,267, 4,656,185, 4,654,357, 4,654,356, 4,654,355, 4,654,335,
4,652,578, 4,652,576, 4,650,874, 4,650,797, 4,649,139, 4,647,585,
4,647,573, 4,647,565, 4,647,561, 4,645,836, 4,639,461, 4,638,012,
4,638,011, 4,632,931, 4,631,283, 4,628,095, 4,626,548, 4,614,825,
4,611,007, 4,611,006, 4,611,005, 4,609,671, 4,608,386, 4,607,049,
4,607,048, 4,595,692, 4,593,042, 4,593,029, 4,591,603, 4,588,743,
4,588,742, 4,588,741, 4,582,854, 4,575,512, 4,568,762, 4,560,698,
4,556,739, 4,556,675, 4,555,571, 4,555,570, 4,555,523, 4,550,120,
4,542,160, 4,542,157, 4,542,156, 4,542,155, 4,542,151, 4,537,981,
4,537,904, 4,536,514, 4,536,513, 4,533,673, 4,526,901, 4,526,900,
4,525,479, 4,524,151, 4,522,949, 4,521,539, 4,520,026, 4,517,188,
4,482,562, 4,474,804, 4,474,803, 4,472,411, 4,466,979, 4,463,015,
4,456,617, 4,456,616, 4,456,615, 4,418,076, 4,416,896, 4,252,815,
4,220,594, 4,190,587, 4,177,280, 4,164,586, 4,151,297, 4,145,443,
4,143,054, 4,123,550, 4,083,968, 4,076,834, 4,064,259, 4,064,258,
4,064,257, 4,058,620, 4,001,421, 3,993,639, 3,991,057, 3,982,010,
3,980,652, 3,968,117, 3,959,296, 3,951,950, 3,933,834, 3,925,369,
3,923,818, 3,898,210, 3,897,442, 3,897,441, 3,886,157, 3,883,540,
3,873,715, 3,867,383, 3,873,715, 3,867,383, 3,691,216,
3,624,126;
[0063] antimicrobial agents as disclosed in U.S. Pat. Nos.
5,902,594, 5,874,476, 5,874,436, 5,859,027, 5,856,320, 5,854,242,
5,811,091, 5,786,350, 5,783,177, 5,773,469, 5,762,919, 5,753,715,
5,741,526, 5,709,870, 5,707,990, 5,696,117, 5,684,042, 5,683,709,
5,656,591, 5,643,971, 5,643,950, 5,610,196, 5,608,056, 5,604,262,
5,595,742, 5,576,341, 5,554,373, 5,541,233, 5,534,546, 5,534,508,
5,514,715, 5,508,417, 5,464,832, 5,428,073, 5,428,016, 5,424,396,
5,399,553, 5,391,544, 5,385,902, 5,359,066, 5,356,803, 5,354,862,
5,346,913, 5,302,592, 5,288,693, 5,266,567, 5,254,685, 5,252,745,
5,209,930, 5,196,441, 5,190,961, 5,175,160, 5,157,051, 5,096,700,
5,093,342, 5,089,251, 5,073,570, 5,061,702, 5,037,809, 5,036,077,
5,010,109, 4,970,226, 4,916,156, 4,888,434, 4,870,093, 4,855,318,
4,784,991, 4,746,504, 4,686,221, 4,599,228, 4,552,882, 4,492,700,
4,489,098, 4,489,085, 4,487,776, 4,479,953, 4,477,448, 4,474,807,
4,470,994, 4,370,484, 4,337,199, 4,311,709, 4,308,283, 4,304,910,
4,260,634, 4,233,311, 4,215,131, 4,166,122, 4,141,981, 4,130,664,
4,089,977, 4,089,900, 4,069,341, 4,055,655, 4,049,665, 4,044,139,
4,002,775, 3,991,201, 3,966,968, 3,954,868, 3,936,393, 3,917,476,
3,915,889, 3,867,548, 3,865,748, 3,867,548, 3,865,748, 3,783,160,
3,764,676, 3,764,677;
[0064] anti-inflammatory agents as disclosed in U.S. Pat. Nos.
5,872,109, 5,837,735, 5,827,837, 5,821,250, 5,814,648, 5,780,026,
5,776,946, 5,760,002, 5,750,543, 5,741,798, 5,739,279, 5,733,939,
5,723,481, 5,716,967, 5,688,949, 5,686,488, 5,686,471, 5,686,434,
5,684,204, 5,684,041, 5,684,031, 5,684,002, 5,677,318, 5,674,891,
5,672,620 5,665,752, 5,656,661, 5,635,516, 5,631,283, 5,622,948,
5,618,835, 5,607,959, 5,593,980, 5,593,960, 5,580,888, 5,552,424,
5,552,422 5,516,764, 5,510,361, 5,508,026, 5,500,417, 5,498,405,
5,494,927, 5,476,876, 5,472,973, 5,470,885, 5,470,842, 5,464,856,
5,464,849, 5,462,952, 5,459,151, 5,451,686, 5,444,043, 5,436,265,
5,432,181, RE034918, 5,393,756, 5,380,738, 5,376,670, 5,360,811,
5,354,768, 5,348,957, 5,347,029, 5,340,815, 5,338,753, 5,324,648,
5,319,099, 5,318,971, 5,312,821, 5,302,597, 5,298,633, 5,298,522,
5,298,498, 5,290,800, 5,290,788, 5,284,949, 5,280,045, 5,270,319,
5,266,562, 5,256,680, 5,250,700, 5,250,552, 5,248,682, 5,244,917,
5,240,929, 5,234,939, 5,234,937, 5,232,939, 5,225,571, 5,225,418,
5,220,025, 5,212,189, 5,212,172, 5,208,250, 5,204,365, 5,202,350,
5,196,431, 5,191,084, 5,187,175, 5,185,326, 5,183,906, 5,177,079,
5,171,864, 5,169,963, 5,155,122, 5,143,929, 5,143,928, 5,143,927,
5,124,455, 5,124,347, 5,114,958, 5,112,846, 5,104,656, 5,098,613,
5,095,037, 5,095,019, 5,086,064, 5,081,261, 5,081,147, 5,081,126,
5,075,330, 5,066,668, 5,059,602, 5,043,457, 5,037,835, 5,037,811,
5,036,088, 5,013,850, 5,013,751, 5,013,736, 500,654, 4,992,448,
4,992,447, 4,988,733, 4,988,728, 4,981,865, 4,962,119, 4,959,378,
4,954,519, 4,945,099, 4,942,236, 4,931,457, 4,927,835, 4,912,248,
4,910,192, 4,904,786, 4,904,685, 4,904,674, 4,904,671, 4,897,397,
4,895,953, 4,891,370, 4,870,210, 4,859,686, 4,857,644, 4,853,392,
4,851,412, 4,847,303, 4,847,290, 4,845,242, 4,835,166, 4,826,990,
4,803,216, 4,801,598, 4,791,129, 4,788,205, 4,778,818, 4,775,679,
4,772,703, 4,767,776, 4,764,525, 4,760,051, 4,748,153, 4,725,616,
4,721,712, 4,713,393, 4,708,966, 4,695,571, 4,686,235, 4,686,224,
4,680,298, 4,678,802, 4,652,564, 4,644,005, 4,632,923, 4,629,793,
4,614,741, 4,599,360, 4,596,828, 4,595,694, 4,595,686, 4,594,357,
4,585,755, 4,579,866, 4,578,390, 4,569,942, 4,567,201, 4,563,476,
4,559,348, 4,558,067, 4,556,672, 4,556,669, 4,539,326, 4,537,903,
4,536,503, 4,518,608, 4,514,415, 4,512,990, 4,501,755, 4,495,197,
4,493,839, 4,465,687, 4,440,779, 4,440,763, 4,435,420, 4,412,995,
4,400,534, 4,355,034, 4,335,141, 4,322,420, 4,275,064, 4,244,963,
4,235,908, 4,234,593, 4,226,887, 4,201,778, 4,181,720, 4,173,650,
4,173,634, 4,145,444, 4,128,664, 4,125,612, 4,124,726, 4,124,707,
4,117,135, 4,027,031, 4,024,284, 4,021,553, 4,021,550, 4,018,923,
4,012,527, 4,011,326, 3,998,970, 3,998,954, 3,993,763, 3,991,212,
3,984,405, 3,978,227, 3,978,219, 3,978,202, 3,975,543, 3,968,224,
3,959,368, 3,949,082, 3,949,081, 3,947,475, 3,936,450, 3,934,018,
3,930,005, 3,857,955, 3,856,962, 3,821,377, 3,821,401, 3,789,121,
3,789,123, 3,726,978, 3,694,471, 3,691,214, 3,678,169,
3,624,216;
[0065] immunosuppressive agents, as disclosed in U.S. Pat. Nos.
4,450,159, 4,450,159, 5,905,085, 5,883,119, 5,880,280, 5,877,184,
5,874,594, 5,843,452, 5,817,672, 5,817,661, 5,817,660, 5,801,193,
5,776,974, 5,763,478, 5,739,169, 5,723,466, 5,719,176, 5,696,156,
5,695,753, 5,693,648, 5,693,645, 5,691,346, 5,686,469, 5,686,424,
5,679,705, 5,679,640, 5,670,504, 5,665,774, 5,665,772, 5,648,376,
5,639,455, 5,633,277, 5,624,930, 5,622,970, 5,605,903, 5,604,229,
5,574,041, 5,565,560, 5,550,233, 5,545,734, 5,540,931, 5,532,248,
5,527,820, 5,516,797, 5,514,688, 5,512,687, 5,506,233, 5,506,228,
5,494,895, 5,484,788, 5,470,857, 5,464,615, 5,432,183, 5,431,896,
5,385,918, 5,349,061, 5,344,925, 5,330,993, 5,308,837, 5,290,783,
5,290,772, 5,284,877, 5,284,840, 5,273,979, 5,262,533, 5,260,300,
5,252,732, 5,250,678, 5,247,076, 5,244,896, 5,238,689, 5,219,884,
5,208,241, 5,208,228, 5,202,332, 5,192,773, 5,189,042, 5,169,851,
5,162,334, 5,151,413, 5,149,701, 5,147,877, 5,143,918, 5,138,051,
5,093,338, 5,091,389, 5,068,323, 5,068,247, 5,064,835, 5,061,728,
5,055,290, 4,981,792, 4,810,692, 4,410,696, 4,346,096, 4,342,769,
4,317,825, 4,256,766, 4,180,588, 4,000,275, 3,759,921;
[0066] analgesic agents, as disclosed in U.S. Pat. Nos. 5,292,736,
5,688,825, 5,554,789, 5,455,230, 5,292,736, 5,298,522, 5,216,165,
5,438,064, 5,204,365, 5,017,578, 4,906,655, 4,906,655, 4,994,450,
4,749,792, 4,980,365, 4,794,110, 4,670,541, 4,737,493, 4,622,326,
4,536,512, 4,719,231, 4,533,671, 4,552,866, 4,539,312, 4,569,942,
4,681,879, 4,511,724, 4,556,672, 4,721,712, 4,474,806, 4,595,686,
4,440,779, 4,434,175, 4,608,374, 4,395,402, 4,400,534, 4,374,139,
4,361,583, 4,252,816, 4,251,530, 5,874,459, 5,688,825, 5,554,789,
5,455,230, 5,438,064, 5,298,522, 5,216,165, 5,204,365, 5,030,639,
5,017,578, 5,008,264, 4,994,450, 4,980,365, 4,906,655, 4,847,290,
4,844,907, 4,794,110, 4,791,129, 4,774,256, 4,749,792, 4,737,493,
4,721,712, 4,719,231, 4,681,879, 4,670,541, 4,667,039, 4,658,037,
4,634,708, 4,623,648, 4,622,326, 4,608,374, 4,595,686, 4,594,188,
4,569,942, 4,556,672, 4,552,866, 4,539,312, 4,536,512, 4,533,671,
4,511,724, 4,440,779, 4,434,175, 4,400,534, 4,395,402, 4,391,827,
4,374,139, 4,361,583, 4,322,420, 4,306,097, 4,252,816, 4,251,530,
4,244,955, 4,232,018, 4,209,520, 4,164,514 4,147,872, 4,133,819,
4,124,713, 4,117,012, 4,064,272, 4,022,836, 3,966,944;
[0067] cholinergic agents, as disclosed in U.S. Pat. Nos.
5,219,872, 5,219,873, 5,073,560, 5,073,560, 5,346,911, 5,424,301,
5,073,560, 5,219,872, 4,900,748, 4,786,648, 4,798,841, 4,782,071,
4,710,508, 5,482,938, 5,464,842, 5,378,723, 5,346,911, 5,318,978,
5,219,873, 5,219,872, 5,084,281, 5,073,560, 5,002,955, 4,988,710,
4,900,748, 4,798,841, 4,786,648, 4,782,071, 4,745,123,
4,710,508;
[0068] adrenergic agents, as disclosed in U.S. Pat. Nos. 5,091,528,
5,091,528, 4,835,157, 5,708,015, 5,594,027, 5,580,892, 5,576,332,
5,510,376, 5,482,961, 5,334,601, 5,202,347, 5,135,926, 5,116,867,
5,091,528, 5,017,618, 4,835,157, 4,829,086, 4,579,867, 4,568,679,
4,469,690, 4,395,559, 4,381,309, 4,363,808, 4,343,800, 4,329,289,
4,314,943, 4,311,708, 4,304,721, 4,296,117, 4,285,873, 4,281,189,
4,278,608, 4,247,710, 4,145,550, 4,145,425, 4,139,535, 4,082,843,
4,011,321, 4,001,421, 3,982,010, 3,940,407, 3,852,468,
3,832,470;
[0069] antihistamine agents, as disclosed in U.S. Pat. Nos.
5,874,479, 5,863,938, 5,856,364, 5,770,612, 5,702,688, 5,674,912,
5,663,208, 5,658,957, 5,652,274, 5,648,380, 5,646,190, 5,641,814,
5,633,285, 5,614,561, 5,602,183, 4,923,892, 4,782,058, 4,393,210,
4,180,583, 3,965,257, 3,946,022, 3,931,197;
[0070] steroidal agents, as disclosed in U.S. Pat. Nos. 5,863,538,
5,855,907, 5,855,866, 5,780,592, 5,776,427, 5,651,987, 5,346,887,
5,256,408, 5,252,319, 5,209,926, 4,996,335, 4,927,807, 4,910,192,
4,710,495, 4,049,805, 4,004,005, 3,670,079, 3,608,076, 5,892,028,
5,888,995, 5,883,087, 5,880,115, 5,869,475, 5,866,558, 5,861,390,
5,861,388, 5,854,235, 5,837,698, 5,834,452, 5,830,886, 5,792,758,
5,792,757, 5,763,361, 5,744,462, 5,741,787, 5,741,786, 5,733,899,
5,731,345, 5,723,638, 5,721,226, 5,712,264, 5,712,263, 5,710,144,
5,707,984, 5,705,494, 5,700,793, 5,698,720, 5,698,545, 5,696,106,
5,677,293, 5,674,861, 5,661,141, 5,656,621, 5,646,136, 5,637,691,
5,616,574, 5,614,514, 5,604,215, 5,604,213, 5,599,807, 5,585,482,
5,565,588, 5,563,259, 5,563,131, 5,561,124, 5,556,845, 5,547,949,
5,536,714, 5,527,806, 5,506,354, 5,506,221, 5,494,907, 5,491,136,
5,478,956, 5,426,179, 5,422,262, 5,391,776, 5,382,661, 5,380,841,
5,380,840, 5,380,839, 5,373,095, 5,371,078, 5,352,809, 5,344,827,
5,344,826, 5,338,837, 5,336,686, 5,292,906, 5,292,878, 5,281,587,
5,272,140, 5,244,886, 5,236,912, 5,232,915, 5,219,879, 5,218,109,
5,215,972, 5,212,166, 5,206,415, 5,194,602, 5,166,201, 5,166,055,
5,126,488, 5,116,829, 5,108,996, 5,099,037, 5,096,892, 5,093,502,
5,086,047, 5,084,450, 5,082,835, 5,081,114, 5,053,404, 5,041,433,
5,041,432, 5,034,548, 5,032,586, 5,026,882, 4,996,335, 4,975,537,
4,970,205, 4,954,446, 4,950,428, 4,946,834, 4,937,237, 4,921,846,
4,920,099, 4,910,226, 4,900,725, 4,892,867, 4,888,336, 4,885,280,
4,882,322, 4,882,319, 4,882,315, 4,874,855, 4,868,167, 4,865,767,
4,861,875, 4,861,765, 4,861,763, 4,847,014, 4,774,236, 4,753,932,
4,711,856, 4,710,495, 4,701,450, 4,701,449, 4,689,410, 4,680,290,
4,670,551, 4,664,850, 4,659,516, 4,647,410, 4,634,695, 4,634,693,
4,588,530, 4,567,000, 4,560,557, 4,558,041, 4,552,871, 4,552,868,
4,541,956, 4,519,946, 4,515,787, 4,512,986, 4,502,989, 4,495,102;
the disclosures of which are herein incorporated by reference.
[0071] Also of interest are analogs of the above compounds. For all
of the above active agents, the active agents may be present as
pharmaceutically acceptable salts, as mentioned above.
Delivery Vehicle Component
[0072] The delivery compositions of the invention are compositions
that are formulated for delivery of an active agent to a topical
location, such as a keratinized skin surface or a mucosal surface
of a mammalian subject, such as a human subject. By keratinized
skin surface is meant a skin location of a subject, i.e., a
location of the external covering or integument of an animal body.
By mucosal surface is meant a location of a subject that includes a
mucosal membrane, such as the inside of the mouth, in the inside of
the nose, etc.
[0073] Because the dermal delivery formulations of the invention
are formulated for delivery to topical location, they are
formulated so as to be physiologically compatible with the topical
location for which they are formulated. Accordingly, when contacted
with the target keratinized skin surface or mucosal surface for
which they are formulated, the delivery compositions do not cause
substantial, if any, physiological responses (such as inflammation
or irritation) that would render the use of the delivery
compositions unsuitable for topical application.
[0074] The delivery compositions of the invention include an amount
of the active agent-calcium phosphate particle complexes included
in a delivery vehicle component. The delivery vehicle component
refers to that portion of the delivery composition that is not the
active agent-calcium phosphate particle complex component.
[0075] The delivery vehicle component of the delivery compositions
of the invention may vary, as desired, where the particular
ingredients of a given delivery vehicle component will depend, at
least in part, on the nature of the particular composition.
Delivery compositions of interest include liquid formulations, such
as lotions (liquids containing insoluble material in the form of a
suspension or emulsion, intended for external application,
including spray lotions) and aqueous solutions, semi-solid
formulations, such as gels (colloids in which the disperse phase
has combined with the dispersion medium to produce a semisolid
material, such as a jelly), creams (soft solids or thick liquids)
and ointments (soft, unctuous preparations), and solid
formulations, such as topical patches. As such, delivery vehicle
components of interest include, but are not limited to: emulsions
of the oil-in-water (O/W) and the water in-oil (W/O) type, milk
preparations, lotions, creams, ointments, gels, serum, powders,
masks, packs, sprays, aerosols or sticks
Lotions
[0076] Lotions are liquid compositions where the viscosity is
50,000 cP or less, such as 10,000 cP or less, as determined using a
Rotational Viscometer, which Measures viscosity by measuring the
running torque of the cylindrical rotors immersed in a sample,
viscosity determination protocol at a temperature of 25.degree. C.,
as described in JIS K 7117: Testing Methods. For Viscosity With A
Rotational Viscometer Of Resins In The Liquid or ASTM D 2196-86:
Test Methods for Rheological Properties on Non-Newtonian Materials
by Rotational (Brookfield) Viscometer.
[0077] Lotion delivery vehicle components of interest may include a
number of different ingredients, including but not limited to:
water, emollients, natural oils, silicone oils, thickening agents
or viscosity modifiers, synthetic or natural esters, fatty acids,
alcohols, humectants, emulsifiers, preservative systems, colorants,
fragrances, etc. Amounts of these materials may range from 0.001 to
99%, such as from 0.1 to 50%, including from 1 to 20% by weight of
the composition, as desired.
[0078] Emollients are compounds that replace or add to lipids and
natural oils in the skin. The term emollient, as used herein, is
intended to include conventional lipid materials (e.g., fats,
waxes, and other water insoluble materials), polar lipids (e.g.,
lipid materials which have been modified to render them more water
soluble), silicones and hydrocarbons. Emollients of interest
include, but are not limited to: diisopropyl adipate, isopropyl
myristate, isopropyl palmitate, ethylhexyl palmitate, isodecyl
neopentanoate, C.sub.12-15 alcohols benzoate, diethylhexyl maleate,
PPG-14 butyl ether, PPG-2 myristyl ether propionate, cetyl
ricinoleate, cholesterol stearate, cholesterol isosterate,
cholesterol acetate, jojoba oil, cocoa butter, shea butter,
lanolin, and lanolin esters.
[0079] Silicone oils may be divided into the volatile and
non-volatile variety. The term "volatile" as used herein refers to
those materials which have a measurable vapor pressure at ambient
temperature. Volatile silicone oils of interest include but are not
limited to: cyclic or linear polydimethylsiloxanes containing from
3 to 9, such as from 4 to 5, silicon atoms. Linear volatile
silicone materials may have viscosities of 5 centistokes or less at
25.degree. C., while cyclic materials may have viscosities of 10
centistokes or less. Nonvolatile silicone oils of interest include,
but are not limited to: polyalkyl siloxanes, polyalkylaryl
siloxanes and polyether siloxane copolymers. The essentially
non-volatile polyalkyl siloxanes of interest include, for example,
polydimethyl siloxanes with viscosities of 5 to 100,000 centistokes
at 25.degree. C.
[0080] Suitable esters include, but are not limited to: alkenyl or
alkyl esters of fatty acids having 10 to 20 carbon atoms, such as
isopropyl palmitate, isopropyl isostearate, isononyl isonanonoate,
oleyl myristate, oleyl stearate, and oleyl oleate; ether-esters,
such as fatty acid esters of ethoxylated fatty alcohols; polyhydric
alcohol esters; ethylene glycol mono and di-fatty acid esters;
diethylene glycol mono- and di-fatty acid esters, polyethylene
glycol (200-6000) mono- and di-fatty acid esters; propylene glycol
mono- and di-fatty acid esters, such as polypropylene glycol 2000
monooleate, polypropylene glycol 2000 monostearate, ethoxylated
propylene glycol monostearate; glyceryl mono- and di-fatty acid
esters; polyglycerol poly-fatty esters, such as ethoxylated
glyceryl monostearate, 1,3-butylene glycol monostearate,
1,3-butylene glycol distearate; polyoxyethylene polyol fatty acid
ester; sorbitan fatty acid esters; and polyoxyethylene sorbitan
fatty acid esters are satisfactory polyhydric alcohol esters; wax
esters such as beeswax, spermaceti, myristyl myristate, stearyl
stearate; sterols esters, of which soya sterol and cholesterol
fatty acid esters are examples thereof. Both vegetable and animal
sources of these compounds may be used. Examples of such oils
include, but are not limited to: castor oil, lanolin oil, C10-18
triglycerides, caprylic/capric triglycerides, sweet almond oil,
apricot kernel oil, sesame oil, camelina sativa oil, tamanu seed
oil, coconut oil, corn oil, cottonseed oil, linseed oil, ink oil,
olive oil, palm oil, illipe butter, rapeseed oil, soybean oil,
grapeseed oil, sunflower seed oil, walnut oil, and the like. Also
suitable are synthetic or semi-synthetic glyceryl esters, such as
fatty acid mono-, di-, and triglycerides which are natural fats or
oils that have been modified, for example, mono-, di- or triesters
of polyols such as glycerin. In an example, a fatty (C.sub.12-22)
carboxylic acid is reacted with one or more repeating glyceryl
groups. glyceryl stearate, diglyceryl diiosostearate,
polyglyceryl-3 isostearate, polyglyceryl-4 isostearate,
polyglyceryl-6 ricinoleate, glyceryl dioleate, glyceryl
diisotearate, glyceryl tetraisostearate, glyceryl trioctanoate,
diglyceryl distearate, glyceryl linoleate, glyceryl myristate,
glyceryl isostearate, PEG castor oils, PEG glyceryl oleates, PEG
glyceryl stearates, and PEG glyceryl tallowates.
[0081] Fatty acids of interest include, but are not limited to:
those having from 10 to 30 carbon atoms, such as pelargonic,
lauric, myristic, palmitic, stearic, isostearic, hydroxystearic,
oleic, linoleic, ricinoleic, arachidic, behenic and erucic
acids.
[0082] Humectants of the polyhydric alcohol-type may also find use
in the compositions, where examples of polyhydric alcohols include,
but are not limited to: glycerol (also known as glycerin),
polyalkylene glycols, alkylene polyols and their derivatives,
including propylene glycol, dipropylene glycol, polypropylene
glycol, polyethylene glycol and derivatives thereof, sorbitol,
hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,
1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and
mixtures thereof. Also of interest are sugars, e.g., glucose,
fructose, honey, hydrogenated honey, inositol, maltose, mannitol,
maltitol, sorbitol, sucrose, xylitol, xylose, etc. When present,
the amount of humectant may range from 0.001 to 25%, such as from
about 0.005 to 20%, including from about 0.1 to 15%, where in some
instances the amount of humectant ranges from 0.5 to 30%, such as
between 1 and 15% by weight of the composition.
[0083] Emulsifiers may also be present in the vehicle compositions.
When present, the total concentration of the emulsifier may range
from 0.01 to 40%, such as from 1 to 20%, including from 1 to.5% by
weight of the total composition. Emulsifiers of interest include,
but are not limited to: anionic, nonionic, cationic and amphoteric
actives. Nonionic surfactants of interest include those with a
C.sub.10-C.sub.20 fatty alcohol or acid hydrophobe condensed with
from about 2 to about 100 moles of ethylene oxide or propylene
oxide per mole of hydrophobe; C.sub.2-C.sub.10 alkyl phenols
condensed with from 2 to 20 moles of alkylene oxide; mono- and
di-fatty acid esters of ethylene glycol; fatty acid monoglyceride;
sorbitan, mono- and di-C.sub.8-C.sub.2O fatty acids; and
polyoxyethylene sorbitan as well as combinations thereof. Alkyl
polyglycosides and saccharide fatty amides (e.g. methyl
gluconamides) are also of interest nonionic emulsifiers. Anionic
emulsifiers of interest include soap, alkyl ether sulfate and
sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates,
alkyl and dialkyl sulfosuccinates, C.sub.8-C.sub.20 acyl
isethionates, C.sub.8-C.sub.20 alkyl ether phosphates,
alkylethercarboxylates and combinations thereof.
[0084] Where desired, preservatives can include in the
compositions, e.g., to protect against the growth of potentially
harmful microorganisms. Preservatives of interest include alkyl
esters of para-hydroxybenzoic acid, hydantoin derivatives,
propionate salts, and a variety of quaternary ammonium compounds.
Specific preservatives of interest include, but are not limited to:
iodopropynyl butyl carbamate, phenoxyethanol, methyl paraben,
propyl paraben, imidazolidinyl urea, sodium dehydroacetate, benzyl
alcohol, benzylhemiformal, benzylparaben,
5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol,
caprylyl glycol, ethylhexylglycerin, phenoxyethanol sorbic acid,
methylparaben, propylparaben, ethylpareben, butylparaben, sodium
benzoate, potassium sorbate, disodium salt of
ethylenediaminetetraacetic acid, chloroxylenol, DMDM Hydantoin,
3-iodo-2-propylbutyl carbamate, chlorhexidine digluconate,
phenoxyethanol, diazolidinyl urea, biguanide derivatives, calcium
benzoate, calcium propionate, caprylyl glycol, biguanide
derivatives, captan, chlorhexidine diacetate, chlorhexidine
digluconate, chlorhexidine dihydrochloride, chloroacetamide,
chlorobutanol, p-chloro-m-cresol, chlorophene, chlorothymol,
chloroxylenol, m-cresol, o-cresol, DEDM Hydantoin, DEDM Hydantoin
dilaurate, dehydroacetic acid, diazolidinyl urea,
dibromopropamidine diisethionate, DMDM Hydantoin, and the like When
present, preservatives may be present in the delivery compositions
in amounts ranging from about 0.01% to about 10% by weight of the
composition.
[0085] Thickening agents or viscosity modifiers may be included in
the delivery compositions. Thickening agents of interest include,
but are not limited to: polysaccharides, such as starches,
natural/synthetic gums and cellulosics. Starches of interest
include, but are not limited to, chemically modified starches, such
as aluminum starch octenylsuccinate. Gums of interest include, but
are not limited to: xanthan, sclerotium, pectin, karaya, arabic,
agar, guar, carrageenan, alginate and combinations thereof.
Suitable cellulosics include, but are not limited to: hydroxypropyl
cellulose, hydroxypropyl methylcellulose, ethylcellulose and sodium
carboxy methylcellulose. Synthetic polymers are still a further
class of effective thickening agent. This category includes
crosslinked polyacrylates such as the Carbomers and polyacrylamides
such as Sepigel.RTM. 305. When present, amounts of the thickener
may range from 0.001 to 5%, such as from 0.1 to 2%, including from
0.2 to 0.5% by weight.
[0086] In some instances, natural or synthetic organic waxes may be
present, e.g., one or more natural or synthetic waxes such as
animal, vegetable, or mineral waxes. In some instances, such waxes
will have a melting point ranging from 20 to 150.degree. C., such
as from 30 to 100.degree. C., including 35 to 75.degree. C.
Examples of such waxes include waxes such as polyethylene or
synthetic wax; or various vegetable waxes such as bayberry,
candelilla, ozokerite, acacia, beeswax, ceresin, cetyl esters,
flower wax, citrus wax, carnauba wax, jojoba wax, japan wax,
polyethylene, microcrystalline, rice bran, lanolin wax, mink,
montan, bayberry, ouricury, ozokerite, palm kernel wax, paraffin,
avocado wax, apple wax, shellac wax, clary wax, spent grain wax,
grape wax, and polyalkylene glycol derivatives thereof such as
PEG6-20 beeswax, or PEG-12 carnauba wax; or fatty acids or fatty
alcohols, including esters thereof, such as hydroxystearic acids
(for example 12-hydroxy stearic acid), tristearin, and tribehenin.
Also of interest are Acrocomia Aculeata Seed Butter, Almond Butter,
Aloe Butter, Apricot Kernel Butter, Argan Butter, Attalea Maripa
Seed Butter, Avocado Butter, Babassu Butter, Bacuri Butter, Bagura
Soft Butter, Baobab Soft Butter, Bassia Butyracea Seed Butter,
Bassia Latifolia Seed Butter, Black Currant Seed Butter, Brazil Nut
Butter, Camelina Butter, Camellia Butter, Candelilla Butter,
Carnauba Butter, Carpotroche Brasiliensis Seed Butter, Chamomile
Butter, Cocoa Butter, Coconut Butter, Coffee Butter, Cotton Soft
Butter, Cranberry Butter, Cupuacu Butter, Grape Seed Butter, Hazel
Nut Butter, Hemp Seed Butter, Horsetail Butter, Illipe Butter,
Irvingia Gabonensis Kernel Butter, Jojoba Butter, Karite Butter,
Kokum Butter, Kukui Butter, Lavender Butter, Lemon Butter, Lime
Butter, Macadamia Butter, Mango Butter, Marula Butter, Monoi
Butter, Mowrah Butter, Mucaja Butter, Murumuru Butter, Olea Butter,
Olive Butter, Orange Butter, Palm Oil, Passion Butter, Phulwara
Butter, Pistachio Butter, Pomegranate Butter, Pumpkin Butter,
Raspberry Butter, Rice Butter, Sal Butter, Sapucainha Butter,
Seasame Butter, Shea Butter, Soy Butter Tamanu Butter, Sunflower
Seed Butter, Sweet almond Butter, Tangerine Butter, Tucuma Seed
Butter, Ucuuba Butter and Wheat Germ Butter.
[0087] Colorants, fragrances and abrasives may also be included in
the delivery compositions. Each of these substances may range from
0.05 to 5%, such as from 0.1 and 3% by weight. Colorants of
interest include titanium dioxide, where appropriate
surface-treated (codified in the Color Index under the reference CI
77,891), manganese violet (CI 77,742), ultramarine blue (CI
77,007), chromium oxide (CI 77,288), hydrated chromium oxide (CI
77,289), ferric blue (CI 77,510), zinc oxide, zirconium dioxide.
Specific colorants of interest inlcude: D & C red no. 19 (CI
45,170), D & C red no. 9 (CI 15,585), D & C red no. 21 (CI
45,380), D & C orange no. 4 (CI 15,510), D & C orange no. 5
(CI 45,370), D & C red no. 27 (CI 45,410), D & C red no. 13
(CI 15,630), D & C red no. 7 (CI 15,850:1), D & C red no. 6
(CI 15,850:2), D & C yellow no. 5 (CI 19,140), D & C red
no. 36 (CI 12,085), D & C orange no. 10 (CI 45,425), D & C
yellow no. 6 (CI 15,985), D & C red no. 30 (CI 73,360), D &
C red no. 3 (CI 45,430), carbon black (CI 77,266), cochineal
carmine lake (CI 75,470), natural or synthetic melanin, and
aluminium lakes.
[0088] Fragrances of interest include: Abies Alba Leaf Oil,
Acetaldehyde, Acetanilid, Acetic Acid, Achillea Millefolium Oil,
Actinidia Chinensis (Kiwi) Fruit Water, Adipic Acid, Agar, Alcohol
Denat., Algin, Aloe Barbadensis Leaf, Amyl Acetate, Amyl Benzoate,
Amyl Cinnamal, Anethole, Anise alcohol, Anthemis Nobilis Flower
Water, Benzaldehyde, Benzyl Alcohol, Betula Alba Oil, Boswellia
Serrata Oil, Butyl Acetate, Butyl Lactate, Calendula Officinalis
Flower Oil, Camellia Sinensis Leaf Water, Camphor, Capsaicin,
Cedrol, Cinnamal, Citral, Citronellol, Citrus Aurantifolia (Lime)
Oil, Citrus Aurantium Dulcis (Orange) Oil, Citrus Grandis
(Grapefruit) Oil, Citrus Tangerina (Tangerine) Peel Oil, Coumarin,
Diacetone Alcohol, Ethyl Cinnamate, Ethyl Ether, Eucalyptus
Caryophyllus (Clove) Flower Oil, Farnesol, Gardenia Florida Oil,
Geranium Maculatum Oil, Hexyl Cinnamal, Hydrogenated Rosin,
Illicium Verum (Anise) Oil, Isoamyl Acetate, Juniperus Mexicana
Oil, Laurus Nobilis Oil, Lavandula angustifolia (Lavender) Oil,
Melaleuca Alternifolia (Tea Tree) Leaf Oil, Melissa Officinalis
Leaf Oil, Mentha Piperita (Peppermint) Oil, Menthol, 2-Naphthol,
Origanum Majorana Leaf Oil, Panax Ginseng Root Extract, Pelargonic
Acid, Pelargonim Graveolens Flower Oil, Pinus Silvestris Cone Oil,
Prunus Armeniaca (Apricot) Kernel Oil, Rosa Canina Flower Oil,
Rosmarinus Officinalis (Rosemary) Leaf Oil, Santalum Album
(Sandalwood) Oil, Thymus Vugaris (Thyme) Oil, Vanillin, Vitis
Vinifera (Grape) Leaf Oil, Zingiber Officinale (Ginger) Root
Oil.
Semi-Solid Delivery Compositions
[0089] Also of interest are semi-solid delivery compositions, such
as gels, creams and ointments. Such compositions may be mixtures of
(in addition to the active agent-calcium phosphate particle
complex) water, water soluble polymers, preservatives, alcohols,
polyvalent alcohols, emulsifying agents, humectants, wax, solvents,
thickeners, plasticizers, pH regulators, water-retaining agents and
the like. Furthermore, such compositions may also contain other
physiologically acceptable excipients or other minor additives,
such as fragrances, dyes, emulsifiers, buffers, antibiotics,
stabilizers or the like. Examples of these types of compounds are
provided above.
Topical Patches
[0090] Also of interest are solid formulations, such as topical
patch formulations. Topical patch formulations may vary
significantly. Topical patch formulations may include an active
agent layer, a support and a release liner. The active agent layer
may include an amount of the active agent-particle complexes in a
matrix, where the matrix may include one or more of: adhesives,
such as pressure sensitive rubber and acrylic acids, hydrogels,
physiologically acceptable excipients or other minor additives,
such as fragrances, dyes, emulsifiers, buffers, antibiotics,
stabilizers or the like. The support may be made of a flexible
material which is capable of fitting in the movement of human body
and includes, for example, plastic films, various non-woven
fabrics, woven fabrics, spandex, and the like. Various inert
coverings may be employed, which include the various materials
which may find use in plasters, described below. Alternatively,
non-woven or woven coverings may be employed, particularly
elastomeric coverings, which allow for heat and vapor transport.
These coverings allow for cooling of the pain site, which provides
for greater comfort, while protecting the gel from mechanical
removal. The release liner may be made of any convenient material,
where representative release films include polyesters, such as PET
or PP, and the like.
Aerosol Compositions
[0091] Also of interest are aerosol compositions formulations to be
administered via inhalation. These aerosol formulations can be
placed into pressurized acceptable propellants, such as
dichlorodifluoromethane, propane, nitrogen, and the like. They may
also be formulated for non-pressured preparations, such as for use
in a nebulizer or an atomizer. In some embodiments, the
formulations are powdered aerosol formulations which include the
active agent bound particles suspended or dispersed in a propellant
or a propellant and solvent. The propellant may be a mixture of
liquefied chlorofluorocarbons (CFCs) which are selected to provide
the desired vapor pressure and stability of the formulation.
Propellants 11, 12 and 114 are the most widely used propellants in
aerosol formulations for inhalation administration. Other commonly
used propellants include Propellants 113, 142b, 152a, 124, and
dimethyl ether. The compound 1,1,1,2-tetrafluoroethane is also a
commonly used propellant for medicinal aerosol formulations. The
propellant may be 40 to 90% by weight of the total inhalation
composition.
Methods of Making Delivery Compositions
[0092] Aspects of the invention further include methods of making
the delivery compositions. While any convenient fabrication
protocol may be employed, in some instances fabrication protocols
include first preparing the active agent-particle complexes.
Following production of the active agent-particle complexes, the
resultant complexes are then combined within the delivery
composition component using any convenient protocol.
[0093] The active agent-particle complexes may be produced using
any convenient protocol. One protocol of interest includes first
producing a liquid composition of the active agent, such as an
aqueous composition of the active agent, and then combining the
liquid composition with an amount of uniform, rigid, spherical,
nanoporous calcium phosphate particles (with agitation where
desired) under conditions sufficient to produce the desired active
agent-particle complexes. As such, in certain embodiments a fluid
composition of unbound particles, e.g., a slurry of unbound
particles in a suitable solvent system (such as an aqueous or
non-aqueous solvent system) is combined with a suitable amount of
active agent.
Particle Pre-Treatment
[0094] As desired, the unbound particles may be pretreated in some
manner prior to combination with the active agent. As such,
preparation of the active agent bound particles may include a
pre-treatment step, such as an initial pH adjustment step. In this
step, the unbound particles are modified by contacting them with
one or more agents, such as a pH adjustment agent, in order to
provide for desired active agent binding to the particles. The
particular nature of the pH adjustment, if employed, varies
depending on the type of active agent that is to be bound to the
particles. One category of active agents of interest are those that
include acidic and/or basic charged moieties and a molecular mass
greater than a few thousand Daltons, e.g., having a mass of 3000
Daltons or greater, such as 5,000 Daltons or greater, e.g., 10,000
Daltons or greater, 25,000 Daltons or greater, 50,000 Daltons or
greater, 75,000 Daltons or greater, 100,000 Daltons or greater,
250,000 Daltons or greater, 500,000 Daltons or greater, 750,000
Daltons or greater, 1,000,000 Daltons or greater. Examples of such
active agents include, but are not limited to proteins, nucleic
acids and polysaccharides. Such active agents may strongly bind to
the calcium and/or phosphate sites of the particles under a broad
range of pH conditions. Accordingly, for these types of active
agents, pH modification may or may not be performed, as desired.
Where pH modification is desired, pH modification may be performed
by using any convenient pH adjustment agent, e.g., an acid or
alkaline agent. pH adjustment agents of interest include, but are
not limited to: lactic acid, glycolic acid, triethanolamine and
sodium hydroxide. In some instances, pH adjustment agents are
selected that do not block the calcium and/or phosphate binding
sites of particles.
[0095] Another category of active agents of interest are those that
include acidic and/or basic charged moieties and a molecular mass
that does not exceed a few thousand Daltons, e.g., having a mass of
2500 Daltons or less, such as 1500 Daltons or less. Examples of
such active agents include, but are not limited to organic acid and
amine compounds. Such active agents bind to the particles at a
specific pH. Pretreatment of the particles by optimizing the pH,
and/or addition of specific ionic compounds into the binding
solution (described in greater detail below) may be employed, as
desired.
[0096] Yet another category of active agents of interest are
water-soluble small molecules with non-charged or weakly charged
moieties. Examples of such compounds include, but are not limited
to: saccharides, glycosides and amino acid derivatives. For this
category of active agents, an aqueous and/or organic solvent
mixture, such as ethanol/water or acetonitrile/water may be
employed for a pretreatment and active agent binding, as
desired.
[0097] Yet another category of active agents of interest are water
soluble small molecules with hydrophobic moieties. For such active
agents, pretreatment may include contacting the particles with
surface modifying agents, e.g., agents that include one or more
charged groups and one or more hydrophobic tails, such as but not
limited to sodium dodecyl sulfate, sodium lauryl sulfate and sodium
lauryl phosphate, and the like.
[0098] Yet another category of active agents of interest are water
insoluble molecules. Examples of water insoluble molecules of
interest include, but are not limited to: amino acid derivatives,
polyphenols, and retinoids. For such active agents, the use of
organic solvents such as ethanol and dimethyl sulfoxide (DMSO) as a
pretreatment agent and/or loading solvent may be employed, as
desired.
[0099] In some instances, particles are pretreated with an ionic
modification agent. Ionic modification agents include, but are not
limited to, calcium ion modification agents, such as CaCl.sub.2,
phosphate ion modification agents, such as sodium phosphate,
etc.
[0100] Following any particle pretreatment step, e.g., as described
above, in some embodiments the particles are subjected to a washing
step. For example, in some instances, it may be desirable to remove
excess salt or ions from the particles by washing, filtering or
decanting the particles prior to active agent binding. Any
convenient wash protocol and fluid may be employed for this
step.
Complex Formation
[0101] Following any pretreatment and/or washing, such as described
above (if necessary), the unbound particles are combined with
active agent to produce active agent bound particles. The active
agent can be either in powder or solution form, as desired. Any
suitable protocol for combining the active agent and the particles
may be employed, such as simple static mixing in a vessel, etc. The
pH of the composition during binding may be selected to provide for
maximum binding, e.g., by employing a pH adjustment agent, such as
described above. For example, in some instances basic active agents
are combined with the particles under basic conditions and acidic
active agents are combined with the particles under acidic
conditions. Therefore, the pH of the complex formation reaction may
range, in some instances from 5 to 14. In certain instances, the pH
is 10 or less, where, depending on the length of time employed for
complex formation, the pH may be selected so as to avoid
substantial particle degradation, e.g., may be selected to be 5.2
or greater.
[0102] As indicated above, any convenient solvent system may be
employed for producing the active agent-particle complexes. As
indicated above, the solvent system employed in binding the active
agent to the particles to produce the active agent-particle
complexes may vary. Solvent systems finding use in preparing the
active agent-particle complexes may be made up of a single solvent
or a plurality of two or more different solvents. Solvents that are
present in solvent systems of interest may be polar (i.e., they
have a dielectric constant of 15 or greater) or non-polar (i.e.,
they have a dielectric constant of less than 15), and protic (such
that they solvate anions (negatively charged solutes) strongly via
hydrogen bonding) or aprotic (i.e., they have sufficiently large
dipole moments to solvate positively charged species via their
dipole).
[0103] Protic solvents of interest include, but are not limited to:
alcohols, such as methanol, ethanol, propanol, isopropyl alcohol,
butanol, pentanol, hexanol, heptanol, octanol, trifluoroethanol,
phenol, benzyl alcohol, glycerin, ethylene glycol, diethylene
glycol; carboxylic acids/amides, such as formic acid, acetic acid,
lactic acid, propionic acid, trifluoroacetic acid, formamide;
amines, such as ammonia, diethylamine, butyl amine, propyl amine;
and water. Aprotic solvents of interest include, but are not
limited to: hydrocarbons, such as pentane, hexanes, heptane,
cyclohexane, methyl cyclohexane, decalin; ketones/aldehydes, such
as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone,
butanone, pentanone, cyclohexanone, benzaldehyde; aromatic
compounds, such as benzene, toluene, trifluorotoluene, xylene,
anisole, chlorobenzene, aniline, N,N-dimethylaniline, benzonitrile;
ethers, such as dimethoxyethane, dimethyl ether, diethyl ether,
diisopropyl ether, methyl t-butyl ether (MTBE), tetrahydrofuran,
dioxane, glyme, diglyme, polyethylene glycol (PEG), PEG esters, PEG
sorbitans, PEG ethers, PEG esters, polypropylene glycol (PPG), PPG
esters, alkoxylated linear alkyl diols, alkoxylated alkyl glucose
ether, PPG alkyl ethers; esters/amides, such as methyl acetate,
ethyl acetate, propyl acetate, butyl acetate, amyl acetate, ethyl
benzoate, benzyl benzoate, dimethyl phthalate, dibutyl phthalate,
dimethylacetamide, dimethylformamide (DMF); nitriles, such as
acetonitrile; carbonates, such as dimethylcarbonate,
diethylcarbonate, propylene carbonate, ethylene carbonate;
halogenated compounds, such as carbon tetrachloride, chloroform,
dichlormethane, dichloroethane, trichloroethane, freon-11,
BMIM-PF.sub.6 ionic liquid; sulfur/Phosphorus-containing compounds,
such as dimethyl sulfoxide (DMSO), carbon disulfide, sulfolane,
examethylphosphramide; and amines, such as pyridine, triethylamine,
N-methylpyrrolidinone (NMP)
[0104] Solvents of interest include, but are not limited to:
alcohol, alcohol denat., benzyl glycol, benzyl laurate, benzyl
laurate/myristate/palmitate, 1,4-butanediol, 2,3-butanediol,
buteth-3, butoxydiglycol, butoxyethanol, butoxyethyl acetate,
n-butyl alcohol, t-butyl alcohol, butyl myristate, butylene glycol,
butylene glycol propionate, butyl ethylpropanediyl ethylhexanoate,
butyl lactate, butyloctanol, butyloctyl benzoate, butyloctyl
salicylate, butyl stearate, butylphthalimide, butyrolactone,
C.sub.12-15 alkyl benzoate, capric acid, caprylic alcohol, cetearyl
octanoate, cetyl stearyl octanoate, chlorobutanol, C.sub.8-12 acid
triglyceride, C.sub.12-18 acid triglyceride, C.sub.9-12 alkane,
C.sub.10-13 alkane, C.sub.13-14 alkane, C.sub.13-15 alkane,
C.sub.14-17 alkane, C.sub.14-19 alkane, C.sub.15-19 alkane,
C.sub.15-23 alkane, C.sub.18-21 alkane, C.sub.8-9
alkane/cycloalkane, C.sub.9-10 alkane/cycloalkane, C.sub.9-11
alkane/cycloalkane, C.sub.9-16 alkane/cycloalkane, C.sub.10-12
alkane/cycloalkane, C.sub.11-14 alkane/cycloalkane, C.sub.11-15
alkane/cycloalkane, C.sub.12-13 alkane/cycloalkane, C.sub.8-10
alkane/cycloalkane/aromatic Hydrocarbons, C.sub.12-15
alkane/cycloalkane/aromatic hydrocarbons, C.sub.9-10 aromatic
hydrocarbons, C.sub.10-11 aromatic hydrocarbons, CD alcohol 19,
chlorinated paraffin, C.sub.7-8 isoparaffin, C.sub.8-9 isoparaffin,
C.sub.9-11 isoparaffin, C.sub.9-13 isoparaffin, C.sub.9-14
isoparaffin, C.sub.9-16 isoparaffin, C.sub.10-11 isoparaffin,
C.sub.10-12 isoparaffin, C.sub.10-13 isoparaffin, C.sub.22-12
isoparaffin, C.sub.11-13 isoparaffin, C.sub.11-14 isoparaffin,
C.sub.12-14 isoparaffin, C.sub.12-20 isoparaffin, C.sub.13-14
isoparaffin, C.sub.13-16 isoparaffin, C.sub.20-40 isoparaffin, coix
lacryma-jobi (Job's Tears) Seed Water, C.sub.6-12
perfluoroalkylethanol, C.sub.10-18 triglycerides,
cycloethoxymethicone, cycloheptasiloxane, cyclohexanedimethanol,
cyclohexasiloxane, cyclomethicone, cyclopentasiloxane,
cyclotetrasiloxane, cyclotrisiloxane, decane, 1,10-decanediol,
decene, decyl alcohol, deodorized kerosene, diacetin, diacetone
alcohol, dibutyl adipate, dibutyloctyl malate, dibutyloctyl
sebacate, dibutyl oxalate, dibutyl phthalate, dibutyl sebacate,
di-C12-15 alkyl maleate, diethoxydiglycol, diethoxyethyl succinate,
diethylene glycol dibenzoate, diethylhexyl adipate diethylhexyl
maleate, diethylhexyl 2,6-naphthalate, diethylhexyl phthalate,
diethylhexyl sebacate, diethylhexyl succinate, diethyl oxalate,
diethyl phthalate, diethyl sebacate, diethyl succinate,
diheptylundecyl adipate, dihexyl adipate, dihexyldecyl sebacate,
diisoamyl malate, diisobutyl adipate, diisobutyl oxalate,
diisocetyl adipate, diisodecyl adipate, diisononyl adipate,
diisooetyl adipate, diisopropyl adipate, diisopropyl oxalate,
diisopropyl sebacate, dimethoxydiglycol, dimethyl adipate, dimethyl
capramide, dimethyl glutarate, dimethyl isosorbide, dimethyl
maleate, dimethyl oxalate, dimethyl phthalate, dimethyl succinate,
dimethyl sulfone, dioctyl adipate, dioctyl succinate,
dioctyldodecyl sebacate, dioxolane, diphenyl methane, di-PPG-3
myristyl ether adipate, dipropyl adipate, dipropylene glycol,
dipropylene glycol dibenzoate, dipropylene glycol dimethyl ether,
dipropyl oxalate, ditridecyl adipate, dodecene, echium plantagineum
seed oil, eicosane, ethoxydiglycol, ethoxydiglycol acetate,
ethoxyethanol, ethoxyethanol acetate, ethylene carbonate, ethyl
ether, ethyl hexanediol, ethylhexyl benzoate, ethyl lactate, ethyl
macadamiate, ethyl myristate, ethyl oleate, ethyl perfluorobutyl
ether, furfural, glycereth-7 benzoate, glycereth-18 benzoate,
glycereth-20 benzoate, glycereth-7 diisononanoate,
glycereth-4,5-lactate, glycereth-5 lactate, glycereth-7 lactate,
glycereth-7 triacetate, glycine soja (soybean) oil, glycofurol,
glycol, hexadecene, hexanediol, 1,2-hexanediol, 1,2,6-hexanetriol,
hexene, hexyl alcohol, hexyldecyl benzoate, hexyldodecyl
salicylate, hexylene glycol, hydrogenated polydecene, hydrogenated
polydodecene, hydroxymethyl dioxolanone, isoamyl acetate,
isobutoxypropanol, isobutyl acetate, isobutyl benzoate, isobutyl
stearate, isocetyl salicylate, isodecyl benzoate, isodecyl
isononanoate, isodecyl octanoate, isodecyl oleate, isododecane,
isoeicosane, isohexadecane, isononyl isononanoate, isooctane,
isopentane, isopentyldiol, isopropyl acetate, isopropyl citrate,
isopropyl laurate, isopropyl myristate, isopropyl palmitate,
isopropyl phthalimide, isostearyl glycolate, isostearyl stearoyl
stearate, laneth-5, lanolin oil, laureth-2 acetate, limonene,
3-methoxybutanol, methoxydiglycol, methoxyethanol, methoxyethanol
acetate, methoxyisopropanol, methoxyisopropyl acetate,
methoxymethylbutanol, methoxy PEG-7, methoxy PEG-10, methoxy
PEG-16, methoxy PEG-25, methoxy PEG-40, methoxy PEG-100, methyl
acetate, methylal, methyl benzoate, methylbutenes, methyl
gluceth-20 benzoate, methyl hexyl ether, methyl lactate, methyl
perfluorobutyl ether, methylpropanediol, methyl pyrrolidone, methyl
soyate, methyl sunflowerseedate, methyl trimethicone, MIBK, mineral
oil, mineral spirits, mixed terpenes, momordica grosvenori fruit
juice, morpholine, mustelic/palmitic triglyceride, neopentyl
glycol, neopentyl glyol dioctanoate, nonocynol-9, octadecane,
octadecene, octane, octene, octyl benzoate, octyldodecyl lactate,
octyldodecyl octyldodecanoate, octyl isononanoate, octyl
isostearate, octyl laurate, octyl palmitate, octyl stearate, oleyl
alcohol, olive oil PEG-6 esters, peanut oil PEG-6 esters, PBG-33
castor oil, PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-12,
PEG-14, PEG-16, PEG-18, PEG-20, PEG-32, PEG-33, PEG-40, PEG-45,
PEG-55, PEG-60, PEG-75, PEG-80, PEG-90, PEG-100, PEG-135, PEG-150,
PEG-180, PEG-200, PEG-220, PEG-240, PEG-350, PEG-400, PEG-450,
PEG-500, PEG-2 benzyl ether, PEG-15 butanediol, PEG-3 methyl ether,
PEG-4 methyl ether, PEG-6 methyl ether, PEG-7 methyl ether, PEG-50
glyceryl cocoate, PEG-20 hydrogenated castor oil, PEG/PPG-1/2
copolymer, PEG/PPG-4/2 copolymer, PEG/PPG-5/30 copolymer,
PEG/PPG-6/2 copolymer, PEG/PPG-7/50 copolymer, PEG/PPG-8/17
copolymer, PEG/PPG-10/70 copolymer, PEG/PPG-17/6 copolymer,
PEG/PPG-18/4 copolymer, PEG/PPG-19/21 copolymer, PEG/PPG-23/17
copolymer, PEG/PPG-23/50 copolymer, PEG/PPG-25/30 copolymer,
PEG/PPG-26/31 copolymer, PEG/PPG-30/33 copolymer, PEG/PPG-35/9
copolymer, PEG/PPG-38/8 copolymer, PEG/PPG-116/66 copolymer,
PEG/PPG-125/30 copolymer, PEG/PPG-160/31 copolymer, PEG/PPG-200/70
copolymer, PEG/PPG-240/60 copolymer, PEG-10 propylene glycol,
1,5-pentanediol, penetaerythrity tetracaprylate/tetracaprate,
pentylene glycol, perfluorocaprylyl bromide, perfluorodecalin,
perfluorodimethylcyclohexane, perfluorohexane,
perfluoromethylcyclopentane, perfluoroperhydrobenzyl tetralin,
perfluoroperhydrophenanthrene, perfluorotetralin, petroleum
distillates, phenoxyisopropanol, phenylpropanol, polyglyceryl-3
diisostearate, polyglyceryl-2 dioleate, polyoxyethylene glycol
dibenzoate, polyperfluoroethoxymethoxy difluoromethyl ether, PPG-3,
PPG-7, PPG-10 butanediol, PPG-2-buteth-3, PPG-3-buteth-5,
PPG-5-buteth-7, PPG-7-buteth-4, PPG-7-buteth-10, PPG-12-buteth-16,
PPG-15-buteth-20, PPG-20-buteth-30, PPG-20 lanolin alcohol ether,
PPG-2 myristyl ether propionate, PPG-2 butyl ether, PPG-3 butyl
ether, PPG-24-glycereth-24, PPG-25-glycereth-22, PPG-10 glyceryl
ether, PPG-55 glyceryl ether, PPG-67 glyceryl ether, PPG-70
glyceryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-2
methyl ether acetate, PPG-2 propyl ether, propanediol, propyl
acetate, propylene carbonate, propylene glycol, propylene glycol
butyl ether, propylene glycol caprylate, propylene glycol
dibenzoate, propylene glycol methyl ether, propylene glycol
myristate, propylene glycol propyl ether, ricinus communis (castor)
seed oil, SD Alcohol 1, SD Alcohol 3-A, SD Alcohol 3-B, SD Alcohol
3-C, SD Alcohol 23-A, SD Alcohol 23-F, SD Alcohol 23-H, SD Alcohol
27-B, SD Alcohol 30, SD Alcohol 31-A, SD Alcohol 36, SD Alcohol 37,
SD Alcohol 38-B, SD Alcohol 38-C, SD Alcohol 38-D, SD Alcohol 38-F,
SD Alcohol 39, SD Alcohol 39-A, SD Alcohol 39-B, SD Alcohol 39-C,
SD Alcohol 39-D, SD Alcohol 40, SD Alcohol 40-A, SD Alcohol 40-B,
SD Alcohol 40-C, SD Alcohol 46, sea water, sesamum indicum (sesame)
oil, shark liver oil, sorbeth-6, sorbeth-20, sorbeth-30,
sorbeth-40, sorbitan trioleate, stearyl benzoate, stearyl
heptaroate, tetradecene, tetradecylpropionates, tetrahydrofurfuryl
acetate, tetrahydrofurfuryl alcohol, thiolanediol, triacetin,
tributyl citrate, tributylcresylbutane, trichloroethane, triethyl
phosphate, trimethylhexanol, 2,2,4-timethylpentane, trimethyl
pentanol hydroxyethyl ether.
[0105] Where desired, the solvent system can be modified with one
or more modification agents, such as buffers, pH adjusters (acid or
base), hydrophilic molecules, hydrophobic molecules or the
molecules which have both hydrophobic groups and hydrophilic groups
(e.g., surfactants). Buffers of interest include, but are not
limited to: HCl/sodium citrate, citric acid/sodium citrate, acetic
acid/sodium acetate, K.sub.2HPO.sub.4/KH.sub.2PO.sub.4,
Na.sub.2HPO.sub.4/NaH.sub.2PO.sub.4, Borax/Sodium hydroxide, as
well as biological buffers, e.g., TAPS
(3{[tris(hydroxymethyl)methyl]amino}propanesulfonic acid), Bicine
(N,N-bis(2-hydroxyethyl)glycine),
Tris(tris(hydroxymethyl)methylamine),
Tricine(N-tris(hydroxymethyl)methylglycine), HEPES
(4-2-hydroxyethyl-1-piperazineethanesulfonic acid),
TES(2-[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), MOPS
(3-(N-morpholino)propanesulfonic acid), PIPES
(piperazine-N,N-bis(2-ethanesulfonic acid), Cacodylate
(dimethylarsinic acid), SSC (saline sodium citrate) and MES
(2-(N-morpholino)ethanesulfonic acid); etc.
[0106] The components and properties of a particular solvent
system, such as pH, composition, temperature, etc., can be selected
in view of one or more properties of the active agent to be
complexed with the particles, where such properties may include
active agent solubility, structure, pKa, logP, etc.
[0107] Following production of the active agent-particle complexes,
the resultant complexes are then combined with the delivery
composition component using any convenient protocol. The particular
protocol employed may vary depending on the nature of the delivery
composition component, where in certain instances the delivery
composition component and active agent loaded particles may be
combined with mixing to produce the desired delivery composition.
While the temperature during combination may vary, in some
instances the temperature is 80.degree. C., such as 40.degree. C.
or less, such as 30.degree. C. or less, e.g., room temperature or
colder. The amount of active agent-particle complexes that is
combined with the delivery vehicle may vary. In some embodiments,
the amount of active agent-particle complexes that is combined with
the delivery vehicle is sufficient to produce a final delivery
composition in which the amount of active agent-particle complexes
ranges from 0.001 to 1000 mg/g, such as 0.1 to 200 mg/g and
including 1 to 50 mg/g active agent-particle complexes per gram of
delivery composition component. In certain embodiments, the
presence of chelating agents is avoided. The pH of formulation is
5.0 or greater, such as 5.5 or greater.
Utility
[0108] The delivery compositions of the invention find use in
methods of delivering active agents to a topical location of a
subject, where the topical location may be a skin surface location
or a mucosal location. In delivering active agents to a topical
location of a subject, delivery compositions of the invention may
deliver the active agent-particle complexes at least into an
epidermal location that is beneath the skin surface of a subject.
As such, embodiments of the invention include methods of delivering
active agent loaded particles into the stratum corneum of a
subject, where the methods may result in delivery of the complexes
into the deep stratum corneum and/or dermis of a subject. By "into
the stratum corneum" is mean that the complexes are delivered to a
region that is at least 1 cell layer below the skin surface. By
"deep stratum corneum" is meant a region that is 2 or more cell
layers below the skin surface, such as 5 or more cell layers below
the skin surface, including 10 or more cell layers below the skin
surface. In some instances, the complexes are delivered to region
of the stratum corneum that is 2 .mu.m or more such as 5 .mu.m or
more and including 15 .mu.m or more below the surface of the
skin.
[0109] Embodiments of the invention include methods of delivering
active agent loaded particles into the stratum corneum of a
subject, where the methods may result in delivery of the complexes
into the dermis of a subject. By "into the dermis" is meant that
the complexes are delivered to a region that is at least 20 cell
layers below the skin surface.
[0110] Upon reaching their target dermal location, in some
instances the active agent bound particles begin to release their
active agent "payload". Release of the active agent from the
particles may occur according to a number of different mechanisms.
For example, the environment of the skin may reverse any binding
interaction of the agent to the particle. In addition to this
mechanism or alternatively to it, the environment of the skin may
break down the calcium phosphate particles (e.g., via dissolution
caused by pH gradient of the skin), such that the uniform, rigid,
spherical, nanoporous particles dissolve under acidic conditions,
e.g., conditions of pH 5 or lower, such as 4.5 or lower, including
4.3 or lower, such as the physiological acidic conditions of the
stratum corneum. The time required for dissolution of particles in
the stratum corneum may vary, and in certain embodiments ranges
from 1 minute to 72 hours, such as 10 minutes to 24 hours and
including 30 minutes to 12 hours, over which time period active
agent is released from the active agent bound particles. Aspects of
the invention include release of all active agent.
[0111] Methods of the invention therefore result in delivery of an
active agent at least into the stratum corneum of a subject. In
some embodiments, the active agent remains in the stratum corneum
to exert its desired activity. In yet other embodiments, the active
agent may exert its desired activity at one or more other target
locations of the body. Additional target locations interest include
additional epidermal regions, such as but not limited to the
stratum lucidum, stratum granulosum, stratum spinusom, stratum
basale and dermis. In certain embodiments, the active agent is
delivered to a region of the dermis. In certain embodiments, the
active agent is delivered to a region below the dermis, e.g., into
sub-cutaneous tissues.
[0112] In some instances the active agent may be systemically
delivered to the subject. When the active agent is systemically
delivered to the subject, therapeutic plasma levels of active agent
are achieved. Therapeutic plasma levels of active agent may vary
depending on the particular active agent and condition being
treated. In certain embodiments, therapeutic active levels that are
achieved range from 0.1 pg to 100 .mu.g, such as 1 pg to 20 .mu.g,
such as 1 ng to 1 .mu.g and including 10 ng to 100 ng.
[0113] In practicing methods of the invention, a delivery
composition is applied to a topical region of a subject and
maintained at the topical region in a manner sufficient to result
in the desired delivery of the active agent to the subject, as
described above. The topical region is, in certain embodiments, a
keratinized skin region. The keratinized skin region, including
hair follicles, sweat glands and sebaceous glands, may be present
at a variety of intact or damaged skin locations, where locations
of interest include, but are not limited to: limbs, arms, hands,
legs, feet; torso, e.g., chest, back, stomach; head, e.g., neck,
face; etc. In certain embodiments, the region will be a head
region, such as a facial region, e.g., forehead, occipital region,
around the mouth, etc. The topical region to which the composition
is applied may vary with respect to area, ranging in certain
embodiments from 1 mm.sup.2 to 300 cm.sup.2 or more, such as from 1
to 50 cm.sup.2, and including from 3 to 10 cm.sup.2.
[0114] In practicing the subject methods, a subject may be
administered a single dose or two or more doses over a given period
of time. For example, over a given treatment period of one month, 1
or more doses, such as 2 or more doses, 3 or more doses, 4 or more
doses, 5 or more doses, etc., may be applied to a topical location
of the subject, where the doses may be applied weekly or daily or
even multiple times per day.
[0115] Delivery of active agent complexes in accordance with the
present invention may impart one or more advantages as compared to
a control which the active agent is not delivered as a complex with
calcium phosphate particles. For example, in some instances the
active agent is stabilized in the calcium phosphate complexes, such
that its activity is preserved. In some instances, the complexing
the active agent with calcium phosphate particle in complexes
according to embodiments of the invention provides for delivery of
the active agent to locations in which it would not normally be
delivered, e.g., delivery into the stratum corneum where delivery
would be limited to the skin surface if that agent were not present
in a calcium phosphate particle complex. In some instances, methods
of the invention result in enhanced penetration of the active agent
as compared to a suitable control. A suitable control may be a
delivery composition that includes the same active agent and
delivery vehicle components, but lacks the uniform, rigid,
spherical, nanoporous calcium phosphate particles. In some
instances, penetration is enhanced as compared to such a control by
a factor of 2-fold or more, such as 5-fold or more, including
10-fold or more. In yet other embodiments, the complexes serve as a
controlled release depot of active agent from the stratum corneum,
thereby providing desired extended release and delivery profiles
for an active agent.
[0116] While the active agent-calcium phosphate complexes have been
described herein primarily in terms of their use for dermal
delivery applications, in some instances they are employed for
other applications. For example, the active agent-calcium phosphate
complexes of the invention find use in some instances in non-dermal
delivery of active agents to a subject. Examples of non-dermal
delivery formulations include, but are not limited to: capsules,
tablets, pills, pellets, lozenges, powders, granules, syrups,
elixirs, solutions, suspensions, emulsions, suppositories, or
sustained-release formulations thereof, or any other form suitable
for administration to a mammal. In some instances, the
pharmaceutical compositions are formulated for administration in
accordance with routine procedures as a pharmaceutical composition
adapted for oral or intravenous administration to humans. Examples
of suitable pharmaceutical vehicles and methods for formulation
thereof are described in Remington: The Science and Practice of
Pharmacy, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa.,
19th ed., 1995, Chapters 86, 87, 88, 91, and 92, incorporated
herein by reference.
[0117] In certain embodiments, methods of delivering calcium into
at least into the stratum corneum are provided. In these methods,
intact calcium phosphate particles of the invention are delivered
into at least the stratum corneum, e.g., as described above. By
"intact" is meant that the particles are full integrity, undamaged
particles. As such, they will not be the same as particles that
have been contacted with a chelating agent, such as EDTA, where the
chelating agent compromises the structure of the particles, e.g.,
by action of the chelating action with the calcium ions. In these
embodiments, the calcium phosphate particles may be free of any
bound active agent, e.g., they are calcium phosphate particles that
are not associated with an active agent. In these embodiments, the
delivery vehicle component may be free of any chelating agent,
e.g., EDTA. These methods find use in delivery calcium into at
least the stratum according for any convenient purpose, and may be
performed on subjects that are desirous of delivering calcium into
at least the stratum corneum. Any of the delivery vehicles
described above may be employed, where those vehicles that are free
of a chelating agent are of interest.
[0118] The subject methods and compositions may be used in a
variety of different kinds of animals, where the animals are
typically "mammals" or "mammalian," where these terms are used
broadly to describe organisms which are within the class mammalia,
including the orders carnivore (e.g., dogs and cats), rodentia
(e.g., mice, guinea pigs, and rats), lagomorpha (e.g., rabbits) and
primates (e.g., humans, chimpanzees, and monkeys). In certain
embodiments, the subjects or patients are humans.
[0119] The following examples are offered by way of illustration
and not by way of limitation.
EXPERIMENTAL
I. Production and Characterization of Uniform, Rigid, Spherical,
Nanoporous Calcium Phosphate Particles
A. Production
[0120] A calcium phosphate nano-crystal slurry was prepared by
dropwise addition of an aqueous phosphate complex solution into an
aqueous calcium complex solution or suspension under controlled
conditions of temperature, pH, pressure, gas, stirring velocity,
reagent concentration, addition rate and aging time. The slurry was
spray dried to form a spherical porous powder by using a pressure
nozzle type spray dryer with an air-liquid fluid nozzle. The dried
powder was sintered at temperature ranging 300 to 900.degree. C.
for a period of time ranging 1 to 24 hours with gas or electric
furnace or kiln.
B. Characterization
[0121] FIGS. 1A and 1B show the porous structure of the resultant 2
micron uniform, rigid, spherical, nanoporous calcium phosphate
particles (produced as described above) using SEM (A)
10,000.times., (B) 50,000.times.. FIGS. 2A and 2B show the outside
and inside structure of the 2 micron uniform, rigid, spherical,
nanoporous calcium phosphate particles (produced in as described
above) using using both SEM (A) and TEM (B) (15000.times.). The
large (25-50 m.sup.2/g) internal and external surface areas are
substantial, allowing for high capacity binding with active agents.
FIG. 3 shows the particle size distribution of the particles, as
determined by Coulter Multi-sizer 3 particle counter and confirmed
by scanning electron microscopy. The average particle size was 2
.mu.m.
TABLE-US-00003 Cytotoxicity US-FDA 21 CFR Part 58 Non Toxic
Mutagenicity Ames Test Non Mutagenic Skin RIPT (Human) Non
Sensitization Irritating
II. Preparation of Active Agent-Calcium Phosphate Particle
Complexes
A. General Binding Guidelines Including Pre-Treatment of Certain
Active Agents
[0122] Calcium phosphate particles bind a broad range of
biomolecules and in some instances stabilizes them. The binding
with calcium phosphate particles is based on ionic interaction. The
functional groups of calcium phosphate particles consist of
positively charged calcium ions (Ca.sup.++), and negatively charged
phosphate ion (PO.sub.4.sup.-3). This means the amount of the
anionized carboxyl group of the biomaterials will be reduced under
acidic conditions. Thus the binding between anionized carboxyl
group of the biomolecules and calcium ion of calcium phosphate
particles will be weakened. The situation is reversed for the
interaction between the cationized amino group of the biomolecule
and phosphate functional group of calcium phosphate particles in
basic conditions.
[0123] The pH and ionic strength directly influence the binding
between calcium phosphate particles and biomaterials. Calcium
phosphate particles have the ability to bind biomaterials with a
broad range of molecular weights (e.g., 200 to 10,000,000) and
isoelectric points (e.g., 2.0 to 12).
[0124] In addition to pH and ionic strength, the molecular weight,
shape, and the orientation of biomaterials also influence the
binding to calcium phosphate particles. For example, BSA with
relatively low molecular weight bind at 90 mg/g and DNA at a
relatively large molecular weight binds to calcium phosphate
particles at the rate of 1 mg/g. The binding capacity of large
biomolecules such as DNA will be determined by the outer surface
area of calcium phosphate particles. To summarize, the main
parameters influencing the binding between calcium phosphate
particles and biomolecules are pH, ionic strength, the
stereochemical effect, and molecular weight.
B. Specific Active Agent-Calcium Phosphate Particle Complexes
1. Influence of pH on Binding
[0125] a. Salicylic Acid
Materials:
[0126] Calcium phosphate particles [0127] Salicylic acid, Fisher
Scientific, Part No. A277-500
Methods:
[0127] [0128] i. 23.2 mg of Salicylic acid was dissolved in 1 ml of
ethanol. [0129] ii. 4 g of calcium phosphate particles were
suspended in 39.8 ml of water and the pH was adjusted close to the
targeted pH with HCl. [0130] iii. 0.2 ml of Salicylic acid solution
(23.2 mg/ml) was mixed in the suspension of calcium phosphate
particles. [0131] iv. The pH was adjusted to each of the target pH
values (11.36, 8.34, 7.47, 7.07, 5.99) with HCl. [0132] v. At each
pH, a 4.8 ml sample was taken from the suspension. All the samples
were centrifuged separately at 2000.times.g for 10 min. [0133] vi.
The absorbance of supernatant was measured at 297 nm (the detection
wavelength for Salicylic acid) by UV spectrophotometer. [0134] vii.
The control was carried out by the same procedures without calcium
phosphate particles.
Results:
[0135] The results are shown in the table below and demonstrate
that Salicylic acid binds to calcium phosphate particles in a pH
dependent manner driven by the pKa of Salicylic acid.
TABLE-US-00004 Salicylic acid pH Bound (ug/g) 11.36 1141.14 8.34
660.4 7.47 97.5 7.07 23.8 5.99 0
b. Polyphenol Complex (PPC) to Calcium Phosphate Particles
Materials:
[0136] Calcium phosphate particles [0137] Polyphenol complex
(PPC)
Methods:
[0137] [0138] i. 33.98 mg of PPC was dissolved in 6.8 ml of water.
[0139] ii. 2 g of calcium phosphate particles were suspended in
19.9 ml of water and the pH was adjusted to pH 9.62 with HCl.
[0140] iii. 0.1 ml of PPC solution (5 mg/ml) was mixed in the
suspension of calcium phosphate particles; a 2 ml sample was taken.
[0141] iv. The pH was adjusted to each of the target pH values
(8.58, 8.07, 7.49, 7.21, 6.75, 6.08) with HCl. [0142] v. At each
pH, a 2 ml sample was taken from the suspension. All the samples
were centrifuged separately at 2000.times.g for 10 min. [0143] vi.
The absorbance of each supernatant was measured at 280 nm (the
detection wavelength for PPC) by UV spectrophotometer. [0144] vii.
The control was carried out by the same procedures without calcium
phosphate particles.
Results:
[0145] Binding capacity of calcium phosphate particles is
summarized in the table below. The results demonstrate that PPC
binding can be carried out at any pH, and is therefore pH
independent.
TABLE-US-00005 pH PPC bound (.mu.g/g) 9.62 242.5 8.58 242.5 8.07
235.0 7.49 215.0 7.21 220.0 6.75 212.5 6.08 197.5
2. Binding Examples of Protein Actives with different Molecular
Weights (MW) and Isoelectric Points (pI) a. Bovine Serum Albumin
(BSA) (MW: 66 KD, pI: 4.7)
Materials:
[0146] Calcium phosphate particles [0147] BSA, lypholized powder,
Fisher Scientific, Catalog No. BP-671-10
Methods:
[0147] [0148] i. 0.5 g of calcium phosphate particles was suspended
in 1 ml of water, pH was adjusted with HCl to approximately 7. The
suspension was mixed for 10 min. [0149] ii. BSA was dissolved in
water and gently mixed to prepare a 20 mg/ml solution. 4 ml of the
BSA solution was added into each suspension of calcium phosphate
particles, and mixed for 30 min. The final pH of the suspension was
determined. [0150] iii. The suspension was centrifuged at
2000.times.g for 5 min. The supernatant was transferred to new
tubes and centrifuged again at 2000.times.g for 5 min. [0151] iv. A
size-exclusion HPLC method was developed to quantify BSA in the
supernatants of the binding suspensions. The separation was
performed using a Phenomenex BioSep.TM.-SEC-S3000 column
(7.8.times.300 mm, 5 .mu.m) in the Shimadzu 10AS system. The mobile
phase was 100% 50 mM phosphate buffer (Na.sup.+, pH 6.8), and
eluted at a rate of 1.4 ml/min. The eluent was monitored at 280 nm.
BSA was observed as a major peak with retention time at about 6.8
min. The quantification of BSA was achieved by external standard
calibration. [0152] v. The control was carried out by the same
procedure without calcium phosphate particles.
Results:
[0153] BSA bound to calcium phosphate particles at 95.1 mg/g.
b. Lactoferrin (MW: 90KD, pI: 8.5)
Materials:
[0154] Calcium phosphate particles [0155] Lactoferrin from human
milk, Sigma Aldrich, Catalog No. 0520-100MG
Methods:
[0155] [0156] i. Lactoferrin solution was prepared in water at 4.98
mg/ml. [0157] ii. 0.3 g of Calcium phosphate particles was
suspended in 1.2 ml of water and mixed for 5 min. [0158] iii. 1.8
ml of Lactoferrin solution at 4.98 mg/ml was added to achieve the
final concentrations at 3.0 mg/ml, and the final volume was 3 ml.
[0159] iv. The suspension was mixed for 30 min, and centrifuged at
5000.times.g for 10 min in a bench top centrifuge. [0160] v. The
absorbance of supernatant was measured at 280 nm (the detection
wavelength for Lactoferrin) by UV spectrophotometer. [0161] vi. The
control was carried out by the same procedures without calcium
phosphate particles. [0162] vii. Lactoferrin bound was calculated
by subtracting the amount of the Lactoferrin detected in the
supernatant from the total initial amount in the binding
suspension.
Results:
[0163] 29.63 mg/g Lactoferrin was determined bound to calcium
phosphate particles at a binding concentration of 2.99 mg/ml.
c. Lysozyme (MW: 14 KD, pI: 10.7)
Materials:
[0164] Calcium phosphate particles [0165] Lysozyme, MP biomedicals
LLC. Product No. ICN10083405 [0166] Phosphoric acid, Fisher
Scientific, Product No. A260500
Methods:
[0166] [0167] i. 364.7 mg of Lysozyme as dissolved in 18.01 ml of
water (20.25 mg/ml). [0168] ii. 0.8 g of calcium phosphate
particles were mixed with 4 ml of water, and the pH of the
suspension was adjusted to neutral with diluted phosphoric acid.
[0169] iii. 4 ml of Lysozyme solution (20.25 mg/ml) was added to
the suspension of calcium phosphate particles to achieve a final
concentration of 10.124 mg/ml, and a final volume of 8 ml. The
final pH was measured. [0170] iv. The suspension was mixed for 30
min, and centrifuged at 2000.times.g for 10 min in a bench top
centrifuge. [0171] v. The absorbance of supernatant was measured at
280 nm (the detection wavelength for Lysozyme) by UV
spectrophotometer. [0172] vi. The control was carried out by the
same procedures without calcium phosphate particles.
Results:
[0173] Lysozyme was determined bound to calcium phosphate particles
at 6.8 mg/g at pH 6.83.
3. Influence of Solvent on Binding
[0174] Adapalene
Materials:
[0175] Calcium phosphate particles [0176] Adapalene, Sekhsaria
Chemicals Limited, India [0177] DMSO, Fisher Scientific, Product
No. D159-4 [0178] Ethanol, Fisher Scientific, Product No.
AC61511-0010
Methods:
[0178] [0179] i. Adapalene was prepared as saturated solutions in
ethanol and DMSO (0.087 mg/ml in ethanol, 20.65 mg/ml in DMSO)
[0180] ii. 0.5 g of calcium phosphate particles were mixed with 5
ml of the Adapalene saturated solution in ethanol or DMSO. [0181]
Iii. The suspensions were mixed for 30 min, and centrifuged at
2000.times.g for 10 min in a bench top centrifuge. [0182] iv. The
absorbance of supernatants were measured at 319 nm (the detection
wavelength for Adapalene) by UV spectrophotometer. [0183] v. The
controls were carried out by the same procedures without calcium
phosphate particles.
Results:
[0184] Binding capacity of Adapalene to calcium phosphate particles
in ethanol is 0.78 mg/g. Binding capacity of Adapalene to calcium
phosphate particles in DMSO is 12.55 mg/g.
C. Example of Pretreatment of Bioactives
[0185] Argireline to calcium phosphate particles was pretreated
with sodium lauryl sulfate
Materials:
[0185] [0186] Calcium phosphate particles [0187] Argireline,
(Acetyl Hexapeptide-8), Lipotec S.A. [0188] Sodium lauryl sulfate
(SLS), Colonial Chemical, Inc.
Methods:
[0188] [0189] i. Argireline was dissolved in water as a 10 mg/ml
solution. [0190] ii. Calcium phosphate particles were mixed with 10
ml of 0.1% SLS for 5 min. The suspension was centrifuged at
2000.times.g for 10 min in the bench top centrifuge, and the
supernatant was removed. The pellet was re-suspended in 20 ml
water, centrifuged at 2000.times.g for 10 min, and the washing
supernatant was discarded. The washing step was repeated twice. The
water contained in the pellet was determined. The final pellet was
used in the binding study. [0191] iii. Calcium phosphate particles
(SLS treated or no SLS treatment) were mixed with water. HCl (or
NaOH) was added to adjust the pH of Calcium phosphate particles
suspension to targeted pH including neutral and pH.about.10. [0192]
iv. Argireline stock at 10 mg/ml was added to each binding
suspensions to be a final concentration of 0.5 mg/ml. After the
suspension was mixed for 30 min, the final pH was measured. [0193]
v. The binding suspensions were centrifuged at 2000.times.g for 10
min in the bench top centrifuge. The supernatants were analyzed
with Refractive Index detector connected to the Shimadzu HPLC 20A
system to quantify the free Argireline in the solution. A
size-exclusion HPLC method was developed to quantify Argireline in
the supernatants of the binding mixtures. The separation was
achieved using a Phenomenex BioSep.TM.-SEC-S3000 column
(7.8.times.300 mm, 5 .mu.m) in the Shimadzu 20A system. The mobile
phase was 100% water, and eluted at a rate of 1 ml/min. The eluent
was monitored at 205 nm or by a refractive index detector
(Shimadzu, Model No. RID-10A). Argireline was observed as a major
peak in the chromatogram with retention time of about 14 min. The
quantification of Argireline was achieved by external standard
calibration. [0194] vi. The Argireline bound was then calculated by
subtracting the amount of Argireline detected in the supernatant
from the total initial amount in the binding suspension.
Results:
TABLE-US-00006 [0195] Calcium phosphate Argireline particles pH
bound (mg/g) SLS treated 7.85 1.19 SLS treated 10.10 2.15 No
pretreatment 7.39 0.09 No pretreatment 10.46 0.05
D. Visualization of Active Agent bound to Calcium Phosphate
Particles
[0196] 0.1 g of calcium phosphate particles was added to 1 ml 0.9%
Rhodamine B in water, and the resultant suspension was spun and the
supernatant was removed. The resultant Rhodamine B-calcium
phosphate particles were dried at 58.degree. C. for 24 hours. The
resultant powder was resuspended in Caprylic/Capric Triglyceride
and imaged via microscopy. The resultant image is shown in FIG. 4A.
FIG. 4B shows calcium phosphate particles without any Rhodamine
B.
E. Additional Active Agent-Calcium Phosphate Complexes
[0197] Using the protocols illustrated above, active agent-calcium
phosphate complexes were produced as summarized in the following
tables. In the following tables, the specific solvent systems are
examples of solvent systems that may be used.
TABLE-US-00007 Classes Active Name Solvent 534-1. Azo Compounds
Sulfasalazine Ethanol 534-1. Diazo Compounds Azaserine Water 536-2.
Carbohydrate derivatives Dextran sulfate sodium salt Water MW 20000
536-2. Carbohydrate derivatives Hyaluronic Acid, Low MW Water
536-2. Carbohydrate derivatives Hyaluronic Acid, High MW Water
536-3. Glycosides Doxorubicin hydrochloride Water (Adriamycin)
536-4. Oxygen-containing hetero Uridine 5'-diphosphoglucose 10 mM
Bis-Tris ring disodium salt Buffer 536-5. Flavon sugar compounds
Riboflavin 5'-monophosphate 10 mM Bis-Tris Buffer 536-5. Flavon
sugar compounds Rutin hydrate Ethanol 540-6. Steroidal hetero
Sodium Cholesteryl Sulfate Ethanol compounds 540-7. Azaporphyrins
Cyanocobalamin Acetonitrile 540-8. Four-membered lactam Cefaclor
Water with a vicinyl halogen 540-9. Nitrogen hetero rings of GYKI
52466 hydrochloride Water more than six members (can include
multiple heteroatoms) 544-10. Hetero ring is six- Thiamine
Pyrophosphate Water membered having two or more ring heteroatoms of
which at least one is nitrogen 544-11. Six-membered hetero
Acesulfame K Acetonitrile ring consists of oxygen, sulfur, nitrogen
and carbon 544-12. Six-membered hetero Methylene Blue Acetonitrile
ring consists of sulfur, nitrogen and carbon 544-13. Six-membered
hetero Furaltadone Dichloromethane ring consists of oxygen,
nitrogen and carbon 544-14. Six-membered hetero Ciclopirox Olamine
Water ring consists of nitrogen and carbon 544-15. Hetero ring is
six- Nicotine Water membered consisting of one nitrogen and five
carbons 548-16. Hetero ring is five- Imiquimod Ethanol membered
having two or more ring hetero atoms of which at least one is
nitrogen 548-18. Hetero ring is three- (1R)-(-)-(10- DMSO membered
having two or more Camphorsulfonyl)oxaziridine ring hetero atoms of
which at least one is nitrogen 549-19. Sulfur containing hetero
Amoxicillin Acetonitrile ring (e.g., thiiranes, etc.) See above.
549-20. Oxygen containing hetero (-)Scopolamine methyl nitrate
Water ring (e.g., oxirane, etc.) See above 549-20. Oxygen
containing hetero Calcein Water ring (e.g., oxirane, etc.) See
above 552-21. Azides AZT (Azidothymidine or Zidovudine) DMSO
552-22. Triphenylmethanes o-Cresolphthalein Complexone 10 mM
Bis-Tris Buffer 552-23. Tetracyclo naphthacene Minocycline
Hydrochloride (HCl), 10 mM Bis-Tris configured ring system having
at Buffer least one double bond between ring members 552-23.
Tetracyclo naphthacene Chlortetracycline HCl Water configured ring
system having at least one double bond between ring members 552-24.
Quinolines, Hydrocarbon Difloxacin HCl Water 552-25. Steroids CHAPS
(3-[(3- Acetonitrile Cholamidopropyl)dimethylammonio]-
1-propanesulfonate) 554-26. Fatty compounds having Lecithin
(L-.alpha. Phosphatidylcholine) Octanol an acid moiety which
contains the carboxyl of a carboxylic acid, salt, ester, or amide
group bonded directly to one end of an acyclic chain of at least
seven uninterrupted carbons. 556-27. Heavy metal, aluminum,
Carboplatin Acetonitrile or silicon organic compounds. 558-28.
Thioimidate esters Sinigrin Hydrate Water 558-29. Imidate esters
Ethyl Benzimidate Hydrochloride DMSO 558-30. Thiocyanate esters
Allyl isothiocyanate Hexane 558-31. Sulfate esters .beta.-Estradiol
3-sulfate sodium salt DMSO 558-32. Sulfonate esters Alizarin Red S
Water 558-33. Phosphorus esters Alendronic Acid Acetonitrile-1M
(phosphonate, phosphonic acid) NaOH 558-35. Nitrate esters or
Norcandil DMSO chalcogen analogues 560-36. Carboxylic acid esters
Methyl Salicylate Ethanol 560-37. Sulfonic acids, salts,
Chondroitin sulfate A sodium salt Water halides 560-38.
Sulfohydroxamate esters Sulfadimethoxine Isopropyl Alcohol or
chalcogen analogues 560-39. Perhydroxamate esters
6-Aminonicotinamide Acetonitrile-1M or chalcogen analogues HCl
562-40. Organic acids Salicylic acid Acetonitrile 562-40. Organic
acids L-Arginine Water 562-40. Organic acids L-Histidine
Acetonitrile-1M HCl 562-40. Organic acids DPHP (Dipalmitoyl
Hydroxyproline) Ethanol 562-40. Organic acids Adapalene DMSO
562-40. Organic acids Ca PCA (Calcidone) Water 562-41. Acid
halides, acid Poly[(isobutylene-alt-maleic acid, Acetonitrile
anhydrides ammonium salt)-co-(isobutylene-alt- maleic anhydride)],
average Mw ~60,000 562-42. Selenium or Tellurium Seleno-DL-cystine
IPA-1M HCl; compounds Acetic Acid-1M HCl 564-43. Ureas Allantoin
DMSO 564-44. Sulfonamides, sulfamides Sumatriptan Succinate
Acetonitrile 564-45. Nitro-containing 2-Nitrophenyl
.beta.-D-glucopyranoside Isopropyl Alcohol compounds 564-46.
Carboxamides Z-L-Asparagine Acetonitrile- Water 564-47. Oxyamines
Methoxyamine hydrochloride Acetonitrile 568-48. Boron, Phosphorus,
Resveratrol Ethanol Sulfur, or Oxygen compounds 568-48. Boron,
Phosphorus, ATP (Adenosine Triphophate) Water Sulfur, or Oxygen
compounds 568-48. Boron, Phosphorus, ADP (Adenosine Diphosphate)
Water Sulfur, or Oxygen compounds 568-48. Boron, Phosphorus, AMP
(Adenosine Monophosphate) Water Sulfur, or Oxygen compounds 568-48.
Boron, Phosphorus, Zoledronic acid Acetonitrile-1M Sulfur, or
Oxygen compounds NaOH 570-49. Halogen containing Diclofenac
Acetonitrile organic compounds 424-50. Lymphokines Gamma Globulins
from bovine blood Water 424-51. Enzyme or coenzyme Thrombin Topical
(Recombinant) Water 424-51. Enzyme or coenzyme Superoxide dismutase
Water 424-52. Extract, body fluid, or Catalase Water cellular
material of undetermined constitution derived from animal is active
ingredient 424-52. Extract, body fluid, or Goat IgG Water cellular
material of undetermined constitution derived from animal is active
ingredient 424-53. Inorganic active Bacitracin zinc salt
Acetonitrile-1M ingredient containing composition, HCl e.g. metal
424-53. Inorganic active Copper phthalocyanine Water ingredient
containing composition, e.g. metal 424-54. Extract or material
Streptomycin sulfate salt Acetonitrile containing or obtained from
a multicellular fungus as active ingredient 435-55. Enzyme (e.g.,
ligases, Sulfatase Water etc.), proenzyme; 435-55. Enzyme (e.g.,
ligases, Phosphatase Water etc.), proenzyme; 435-55. Enzyme (e.g.,
ligases, Lysozyme Water etc.), proenzyme; 435-56. Virus or
bacteriophage, Bacteriophage CE6 Water; except for viral vector or
.lamda. phage for delivery of T7 RNA 20 mM Na bacteriophage vector;
polymerase Phosphate composition thereof; Buffer 435-57.
Micro-organism Ampicillin sodium Water 435-57. Micro-organism
Gentamicin sulfate from Water Micromonospora purpurea 530-58.
Peptides of 3 to 100 Lys-Lys-Lys Acetonitrile amino acid residues
530-58. Peptides of 3 to 100 Argireline Water amino acid residues
530-59. Peptides containing N-Acetylmuramyl-L-alanyl-D- Ethanol
unnatural amino acid residues or isoglutamine hydrate (Muramyl
derivatives Dipeptide) 530-60. Peptides containing non- Cyclosporin
A Hexane linear or heterogeneous backbone elements 530-61.
Peptide-like structures Boc-Gly-Lys-Arg-7-amido-4- Acetonitrile
containing terminal methylcoumarin hydrochloride
functionalization(s) 530-62. Proteins, i.e., more than Lactoferrin
(human precursor Water 100 amino acid residues reduced) 530-62.
Proteins, i.e., more than BSA Water 100 amino acid residues 530-62.
Proteins, i.e., more than Ovalbumin Water 100 amino acid residues
530-62. Proteins, i.e., more than Phycoerythrin Water 100 amino
acid residues 426. Food or edible material: Fermented soybean
extract Water; processes, compositions, and Glycerin products 426.
Food or edible material: Aloe Vera (Botanivera 1-200C) Water
processes, compositions, and products 426-63. Product for promoting
the Ascorbic Acid (Vitamin C) Water effect of an alimentary canal
microorganism Product with added vitamin or derivative thereof for
fortification 426-63. Product for promoting the Sodium Ascorbyl
Phosphate (Stay- Water effect of an alimentary canal C)
microorganism Product with added vitamin or derivative thereof for
fortification 426-63. Product for promoting the Potassium Ascorbyl
Tocopheryl Water effect of an alimentary canal Phosphate
(Sepivital) microorganism Product with added vitamin or derivative
thereof for fortification 426-63. Product for promoting the
Disodium Ascorbyl Sulfate (VC-SS) Water; effect of an alimentary
canal Acetonitrile microorganism Product with added vitamin or
derivative thereof for fortification 426-63. Product for promoting
the Ubiquinol Hexane effect of an alimentary canal microorganism
Product with added vitamin or derivative thereof for fortification
426-64. Predominantly Ursolic Acid DMSO hydrocarbon compounds
containing cyclic carbon rings; three-, four-, five-, six- or more
membered rings. Loading Optimum Structural No Actives Solvent pH
classes 1 Ascorbic acid Water >8.12 Sugar acids 2 Salicylic Acid
Ethanol/water 4.03-7.90 Aromatic acids 3 Hyaluronic acid Water 7
Polysaccharide Sodium salt 4 Hyaluronic acid Water 7 Polysaccharide
Sodium salt 5 Argireline Water 6.7-7.8 Peptides Water 7.8 Water 6.4
6 Fermented Soybean Glycerin 7 Proteins Extract 7 Sepivital (dl-a-
Water 7 Vitamin tocopheryl 2 L derivatives ascorbyl phosphate) 8
Sepilift DPHP Ethanol Amino acid
(dipalmitoyl derivatives hydroxyproline) 9 Resveratrol
Ethanol/water 10 Polyphenol 10 Bovine serum albumin Water 7
Proteins 11 Chlortetracycline Water pH 7-8.5 Tetracycline
antibiotic, 12 Ciclopirox Olamine Water 7 Alkaloids Water pH 8.5
Water pH 8.5 Water pH 9.1 Water pH 8.9 13 Adapalene Ethanol 11
Retinoids Ethanol 7 DMSO 7 14 Imiquimod Ethanol 11 Alkaloids
Ethanol 70.8 15 Adriacin Water 16 Alpha lipoic acid Water 17 Green
tea polyphenol Water Polyphenol 18 Matrixyl Acetate Water Peptide
(PalmitoylPentapeptide, PAL-Lys-Thr-Thr- Lys-Ser) 19 Oleic acid No
solvent Fatty acid 20 Oleyl oleate No solvent Fatty acid 21 Dextran
Water polysaccharide 22 Ascorbic acid Water Vitamin C glucoside
derivative
III. Release of Active Agent
A. pH Dependent Release
1. Lysozyme
[0198] In the stratum corneum, the pH ranges from approximately 4.3
to 5.0 with pH decreasing with stratum corneum depth. To study
calcium phosphate particle release active agent at conditions
analogous to skin, two lysozyme calcium phosphate complexes were
exposed to buffers of ph 4.8 (0.5 M sodium acetate) and 7.0 (10 mM
Bis Tris) for 8 hours. The buffers flowed through the samples at a
rate of 1 mL/hr and were collected hourly and analyzed for lysozyme
release by monitoring the peak at 280 nm by UV spectrometer. An
equivalent mass of lysozyme Calcium phosphate particles complex was
vortexed in pH. 4.8 buffer to estimate the total available lysozyme
in the sample. At pH 4.8, lysozyme was observed to quickly release
from the calcium phosphate particles with most of the lysozyme
releasing within the first hour. In contrast, at pH 7, no lysozyme
is observed released from calcium phosphate particles over 8
hours.
B. Release via Hydroxysome Degradation
1. Calcium Phosphate Particles Degrade at pH 4.8
[0199] 50 mg of calcium phosphate particles were incubated in 2 mL
at two pHs: 4.8 (0.5 mM sodium acetate) and 7.1 (0.1mM Bis Tris)
and the solutions place on a rotator for 96 hours at room
temperature. The samples were centrifuged and the pellet dried and
weighed. The percent weight loss of calcium phosphate particles at
pH 4.8 and 7.1 was 12% and 3%, respectively. The buffering capacity
of this closed system limited the complete dissolution of the
calcium phosphate particles. Dissolution was then studied in a
flow-through system with the same buffer whereby the solution was
slowly (5 mL/hr) flowed through the sample (50 mg) with gentle
agitation of the sample followed by collection and drying of the
calcium phosphate particle pellet. After 72 hours, the percent
weight loss of calcium phosphate particle pellet at pH 4.8 and 7.1
was 31% and 3%, respectively. These results demonstration that
calcium phosphate particles dissolve at low pH and this dissolution
is a function of the pH and buffering capacity of the solution.
C. Active Agent is Reversibly Bound to Calcium Phosphate Particles
and Release does not Alter Activity of Active Agent
1. BSA Calcium Phosphate Complex
[0200] BSA-calcium phosphate complexes were prepared as above. The
resultant complexes were washed with water and then treated with
0.2 M sodium phosphate to release any bound BSA.
Materials:
[0201] Calcium phosphate particles, [0202] BSA, lypholized powder,
Fisher Scientific, Catalog No. BP-671-10
Methods:
[0202] [0203] i. 0.1170 g of BSA was dissolved in 11.7 ml of water
as a solution of 10 mg/ml. [0204] ii. 0.5 g of calcium phosphate
particles were mixed with 5 ml of BSA solution at 10 mg/ml. The
suspension was mixed for 30 min and the final pH was determined to
be neutral. [0205] iii. The suspension was centrifuged at
2000.times.g for 10 min. The supernatant was transferred to new
tubes and centrifuged again at 2000.times.g for 10 min. [0206] iv.
The final supernatant was analyzed with Shimadzu 10A HPLC system to
quantitate BSA and calculate the binding. [0207] v. The pellet from
5 ml of binding suspension was mixed with 0.8 ml of water, and
centrifuged at 2000.times.g for 10 min. The rinsed pellet was mixed
again with 0.8 ml of water and centrifuged at 2000.times.g for 10
min. [0208] vi. The final rinsed pellet was mixed with 2 ml of 500
mM sodium phosphate buffer (pH 6.8) and 2.235 ml of water to
release BSA in a suspension with 200 mM sodium phosphate. The
release suspension was centrifuged at 2000.times.g for 10 min. The
supernatant was analyzed with Shimadzu 10A HPLC system to
quantitate BSA. [0209] v. The BSA quantitation was achieved using a
Phenomenex BioSep.TM.-SEC-S3000 column (7.8.times.300 mm, 5 .mu.m)
in the Shimadzu 10AS system. The mobile phase was 100% 50 mM
phosphate buffer (Na.sup.+, pH 6.8), and eluted at a rate of 1.4
ml/min. The eluent was monitored at 280 nm. BSA was observed as a
major peak with retention time at about 6.8 min. The quantification
of BSA was achieved by external standard calibration. [0210] vi.
The control was carried out by the same procedures without calcium
phosphate particles.
Results:
[0211] The released BSA was analyzed with HPLC and determined to be
identical to an unbound control (retention time at 6.85 min),
demonstrating that binding and release to calcium phosphate
particles did not impact BSA integrity.
2. Sodium Tocopheryl Phosphate Calcium Phosphate Complex
Materials:
[0212] Calcium phosphate particles [0213] Sodium Tocopheryl
Phosphate (TPNa), Showa Denko KK [0214] Ethanol, Fisher Scientific,
Product No. AC615090020
Methods:
[0214] [0215] i. 20 mg of TPNa was dissolved in 40 ml of water by
gently mixing (0.5 mg/ml). [0216] ii. 3 g of calcium phosphate
particles was mixed with 30 ml of TPNa solution at 0.5 mg/ml, and
mixed for 30 min. [0217] iii. The binding suspension was
centrifuged at 2000.times.g for 10 min. The supernatant was
transferred to new tube, and centrifuge again at 2000.times.g for
10 min to clarify. The final supernatant was analyzed with an UV
spectrophotometer at 286 nm to quantitate free TPNa and calculate
the binding. Approximately 100% of TPNa in the binding suspension
was attached to calcium phosphate particles. [0218] iv. The pellet
of TPNa calcium phosphate complex was re-suspended in 60% ethanol
to release the bound TPNa. [0219] v. The release suspension in 60%
ethanol was centrifuged at 2000.times.g for 10 min. The supernatant
was analyzed with an UV spectrophotometer at 286 nm to quantitate
free TPNa released.
Results:
[0220] The released TPNa was analyzed with UV spectroscopy and
determined to be identical to an unbound control, demonstrating
that binding and release to calcium phosphate particles did not
impact TPNa integrity.
IV. Examples of Formulations
1. Calcium Phosphate Particle-Riboflavin Monophosphate Ointment
Formulation
TABLE-US-00008 [0221] Trade Name INCI Name w/w % 1 Bee wax Bee wax
5.00 2 SonneNatural .TM. Glyceride oils 74.66 3 Protachem IPP
Isopropyl Palmitate 15.00 4 Capmul MCM Glyceryl 3.33
Caprylate/Caprate 5 Purified Water Water 1.00 6 calcium
Hydroxyapatite 1.00 phosphate particles 7 Riboflavin Riboflavin
0.0077 Monophosphate monophosphate
[0222] Procedure: [0223] Step 1. In a beaker add Bee wax and
Protachem IPP. Start to heat to 70.degree. C.-75.degree. C. until
uniform. Cool to 50.degree. C. Add SonneNatural.TM. and Capmul MCM.
Mix until uniform. [0224] Step 2. In a separate beaker add 1% water
and Riboflavin monophosphate. Mix at R.T until dissolved. Add
calcium phosphate particle (adjust pH with lactic acid to pH 7).
Spin for 10 minutes at 500 RPM. [0225] Step 3. Transfer Step 1 to
Step 2 under room temperature. Mix until uniform
B. Stability of Active Agent in Formulation
1. Vitamin C
[0226] a. Methods:
[0227] 11.9 mg of ascorbic acid was dissolved in 30 ml of water. 2
g of 2 .mu.m calcium phosphate particles were suspended in 19.5 ml
of water and the pH was adjusted to pH 7.14 with HCl. 0.5 ml of
ascorbic acid solution (0.40 mg/ml) was mixed in the suspension of
calcium phosphate particles, which reduced the pH to 7.05. The
suspension (pH 7.05) of calcium phosphate particles including 10
.mu.g/ml of ascorbic acid was incubated at 50.degree. C. for 0.5 to
5 hours. The heat-denaturation of ascorbic acid was terminated by
cooling the suspension in an ice bath for 15 minutes. In order to
release bound ascorbic acid from calcium phosphate particles to
measure the stabilization effect, the pH of each suspension was
adjusted to pH 5 with HCl and centrifuged at 3,000 rpm for 10
minutes. The supernatant obtained was measured at 265 nm. As a
control, a 10 .mu.g/ml of ascorbic acid solution was also incubated
and measured by the same procedures without calcium phosphate
particles. The activity of ascorbic acid was calculated by the
following formula:
The activity of ascorbic acid (%)=(A.sub.265nm of the supernatant
after incubation/A.sub.265nm of the ascorbic acid before
incubation).times.100
The same procedures were repeated with 10 .mu.m calcium phosphate
particles. b. Results
[0228] The results are summarized in the table below. The activity
of Ascorbic acid was reduced to 36% by incubation at 50.degree. C.
for 0.5 hrs; this activity was increased to 85% when ascorbic acid
was attached to 2 .mu.m calcium phosphate particles during the same
period. The ascorbic acid without calcium phosphate particles was
totally denatured with no activity after the incubation at
50.degree. C. for 3 hrs. However, the ascorbic acid bound to 2
.mu.m calcium phosphate particles had 48% activity at 50.degree. C.
for the same 3 hr period.
TABLE-US-00009 Time (hrs) Control (%) 2 um (%) 0 100 100 0.5 36 85
2 18 59 3 0 48 5 0 35
C. In order to achieve stability of the active in the calcium
phosphate complex in final formulation, it may be necessary to add
additional free active to the solvent system depending on the
solubility of the solvent system used.
V. Delivery Studies
[0229] 1. Delivery into Stratum Corneum in Human Skin
[0230] A suspension of calcium phosphate particles in water at a
concentration was applied to a forearm of a living human by rubbing
for 10 seconds (FIG. 5). Tape stripping of the first, second and
third layers of the stratum corneum was then performed. The calcium
phosphate particles penetrated to the third layer of the stratum
corneum.
2. Delivery into Lower Layers of Stratum Corneum in Mouse Skin
[0231] Calcium phosphate particles penetrate the stratum cornuem
and penetrate further into the lower layers as the particle
disintegrates into smaller substituent parts. Calcium phosphate
particles were no longer intact after 7 hours and were no longer
spherical, indicating loss of the integrity of the particles.
a. Materials:
[0232] 2 .mu.m calcium phosphate particles were used.
b. Preparation:
[0233] The calcium phosphate particles were suspended in 70%
Ethylene glycol and 30% Ethanol to make a 10% suspension. The
resultant suspension was topically applied on the skin surface of
hairless mice (1.times.1 cm area). During the application, mice
were given anesthetic. The first application (0.2 ml) was
administrated and left on, the second application was administrated
4 hours later at the same place and for the same amount. Seven
hours from the first application the skin was removed, and treated
by the Ca.sup.++. Localization method followed by EM
techniques.
c. Results:
[0234] Prior to treatment with calcium phosphate particles,
examination of the epidermis reveals only in the areas of Stratum
granulosum, with no detectable Ca.sup.++ in stratum cornum (FIG.
6). After topical application of calcium phosphate particles as
described above, calcium phosphate particles can be seen in the
stratum corneum (FIG. 7A), with the smallest particles moving into
deeper layers (FIG. 7B).
3. Active Agent Detection in the Stratum Corneum
[0235] a. Purpose of Study
[0236] The purpose of this study was to detect active agent
(chlorotetracycline (CTC)) in the stratum corneum after the topical
application of active agent (CTC) attached to 2 .mu.m uniform,
rigid, spherical; nanoporous calcium phosphate particles, as
described in
[0237] Example I, above. Chlortetracycline (CTC from Sigma, part
#C-4881) was selected because it allows the visualization of CTC by
fluorescence and is thus detectable by confocal microscopy within
the stratum corneum.
b. Preparation
[0238] A CTC solution was made by dissolving 80 mg of CTC in 10 ml
of water. The un-dissolved CTC was removed by centrifugation at
3,000 rpm for 10 min. 200 mg of particles were mixed with 2 ml of
the CTC solution and vortexed for 1 min. The free CTC was removed
by 3 cycles of washing with water followed by centrifugation for 10
min at 3,000 rpm. The resultant CTC bound particles were suspended
in water at 1:10 dilution rate.
c. Topical Application
[0239] The suspension produced in 3.b above (approximately 0.2 ml)
was topically applied onto the skin of hairless mice (1.times.1 cm
area). During the application, mice were given anesthetic. After 7
hours their skins were examined using confocal microscopy (at 510
nm wavelength emission excited at 380 nm wavelength).
d. Results
[0240] The resultant confocal microscopy image is shown in FIG. 8
(magnification is 300.times. in FIG. 8). The representative image
shown in FIG. 8 shows that CTC fluorescence (purple) penetrates the
skin and is mainly localized in the stratum corneum.
4. Tape-Stripping Analysis of Topical Application of
STAY-C50-Calicum Phosphate and Lysozyme-Calcium Phosphate Complexes
Demonstrate Delivery into the Stratum Corneum
[0241] The purpose of this study was to detect the distribution of
actives in the stratum corneum following topical application of the
active-calcium phosphate particles
[0242] Method: The distribution of STAY C50 within the stratum
corneum was assessed by serial tape stripping of the skin to which
a STAY C50-calcium phosphate particle formulation was applied. An
application site on the forearm of a human subject was marked and
200 .mu.l of the formulation spread by spatula. The site was
allowed to dry for 10 minutes and then followed by ten pre-weighed
tape stripping using strips of (3 in.sup.2) applied to the
application site. STAY C50 was extracted from the tape strips by
sonicating the samples in water for 30 minutes and analyzing the
samples by HPLC. The tape strips showed delivery of STAY-C50 to the
10th layer of stratum corneum (FIG. 9).
[0243] Method: The distribution of lysozyme within the stratum
corneum was assessed by serial tape stripping of the skin to which
a lysozyme-calcium phosphate particle formulation was applied. An
application site on the forearm of a human subject was marked and
200 .mu.l of the formulation spread by spatula. The site was
allowed to dry for 10 minutes and then followed by ten pre-weighed
tape stripping using strips of (3 in.sup.2) applied to the
application site. Lysozyme was extracted from the tape strips by
sonicating the samples in water for 30 minutes and analyzing the
samples by HPLC. Lysozyme was detected to a depth of 6 tape strips
(FIG. 10).
5. Controlled Slow Release of Active Agents by Franz Cell
[0244] Purpose: The purpose of this study was to detect riboflavin
from riboflavin attached to calcium phosphate particles.
Methods:
[0245] Circular 6 cm.sup.2 discs of full-thickness pig skin were
cut from a larger abdominal specimen. Fat was removed from the
dermis-side by scissors and the skin was stored at -20.degree. C.
until use. The skin was affixed between the two compartments of the
glass diffusion cell (Laboratory Glass Apparatus, Model
#LG-1084-LPCT). This allowed an exposed skin area of 5 cm.sup.2
over a receptor compartment volume of 4.5 ml. The diffusion cell
was maintained at 37.degree. C.
[0246] Penetration Conditions [0247] Topical application intervals
were 8 and 16 hrs. The cells were covered with parafilm and
shielded from light by aluminum wrap. A receptor fluid of phosphate
buffered saline (PBS) was spun at 60 rpm.
[0248] Applied Formulations [0249] Riboflavin monophosphate-calcium
phosphate particles were prepared to deliver 0.35-1.15 mg
riboflavin (20-38% suspensions). [0250] Riboflavin monophosphate in
PBS was prepared at 1.5 mg/mL to deliver 0.3-0.45 mg riboflavin.
[0251] Formulations were applied by pipette in volumes of 50-100
.parallel.l. Riboflavin-calcium phosphate complex applications were
allowed to air dry and then equal volume of 0.5 M sodium acetate
buffer was pipetted onto the application site. Controls consisted
of equivalent applications of riboflavin without calcium phosphate
particles.
[0252] Sample Collection [0253] The skin surface, while still
retained in the diffusion cell, was washed twice with 1 mL PBS each
time. The skin was removed from diffusion cell and dried and
analyzed.
[0254] Sample Analysis [0255] Washes and Receptor fluid: The
approximate volume of the fluids was determined. The samples were
spun at 10,000 rpm for 30 seconds and the calcium phosphate
particles separated, dried and weighed. The supernatant was then
removed and analyzed by UV spectrometer. If the UV absorbance was
saturated (over >2.0), the samples were diluted with water. The
UV absorbance value at 370 nm was recorded. [0256] Skin: The skin
was minced and mixed with 5 ml of 10% trichloracetic acid solution.
The sample was sonicated with ultrasonic apparatus at 50.degree. C.
for 1 hour. The sample was centrifuged at 10,000 rpm for 10
minutes, the supernatant removed and analyze by UV spectrometer. If
the UV absorbance was saturated (over >2.0), samples were
diluted with water. The maximum UV absorbance value at 370 nm was
recorded.
Results
[0257] As detected by the appearance of riboflavin metabolite in
the receptor fluid after 8 and 16 hours, riboflavin penetrated
through skin from both the aqueous solution and from calcium
phosphate particle complex. The calcium phosphate particle complex
caused a slower release of the active. The results are shown
graphically in FIG. 11.
[0258] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
[0259] Accordingly, the preceding merely illustrates the principles
of the invention. It will be appreciated that those skilled in the
art will be able to devise various arrangements which, although not
explicitly described or shown herein, embody the principles of the
invention and are included within its spirit and scope.
Furthermore, all examples and conditional language recited herein
are principally intended to aid the reader in understanding the
principles of the invention and the concepts contributed by the
inventors to furthering the art, and are to be construed as being
without limitation to such specifically recited examples and
conditions. Moreover, all statements herein reciting principles,
aspects, and embodiments of the invention as well as specific
examples thereof, are intended to encompass both structural and
functional equivalents thereof. Additionally, it is intended that
such equivalents include both currently known equivalents and
equivalents developed in the future, i.e., any elements developed
that perform the same function, regardless of structure. The scope
of the present invention, therefore, is not intended to be limited
to the exemplary embodiments shown and described herein. Rather,
the scope and spirit of present invention is embodied by the
appended claims.
* * * * *