U.S. patent application number 16/991536 was filed with the patent office on 2021-02-18 for articles and methods for administration of therapeutic agents.
This patent application is currently assigned to Massachusetts Institute of Technology. The applicant listed for this patent is The Brigham and Women's Hospital, Inc., Massachusetts Institute of Technology. Invention is credited to Joshua Korzenik, Robert S. Langer, Christoph Winfried Johannes Steiger, Carlo Giovanni Traverso.
Application Number | 20210046011 16/991536 |
Document ID | / |
Family ID | 1000005208621 |
Filed Date | 2021-02-18 |
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United States Patent
Application |
20210046011 |
Kind Code |
A1 |
Traverso; Carlo Giovanni ;
et al. |
February 18, 2021 |
ARTICLES AND METHODS FOR ADMINISTRATION OF THERAPEUTIC AGENTS
Abstract
Articles and methods for delivering a therapeutic agent to a
subject are described. These articles and methods may be useful, in
some cases, for the delivery of therapeutic agents to the colon of
a subject. In some embodiments, an article is configured to release
a secretion inducing agent e.g., to stimulate the release of
intestinal fluids. The article, in some embodiments, comprises a
therapeutic agent such that the stimulated release of intestinal
fluid increases the amount of therapeutic agent available for
absorption by the colon. For example, in some embodiments, the
articles and methods described herein advantageously promote
increased absorption of therapeutic agents in subjects as compared
to traditionally administered therapeutic agents without additional
components such as a secretion inducing agent. In some embodiments,
articles and methods described herein may increase the motility of
the colon of a subject. The increase in contractions and movement
of fluidic in the colon caused by increase motility may
advantageously facilitate the dissolution or absorption of the
therapeutic agent.
Inventors: |
Traverso; Carlo Giovanni;
(Newton, MA) ; Korzenik; Joshua; (Waban, MA)
; Langer; Robert S.; (Newton, MA) ; Steiger;
Christoph Winfried Johannes; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology
The Brigham and Women's Hospital, Inc. |
Cambridge
Boston |
MA
MA |
US
US |
|
|
Assignee: |
Massachusetts Institute of
Technology
Cambridge
MA
The Brigham and Women's Hospital, Inc.
Boston
MA
|
Family ID: |
1000005208621 |
Appl. No.: |
16/991536 |
Filed: |
August 12, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62885450 |
Aug 12, 2019 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2013 20130101;
A61K 9/4858 20130101; A61K 9/4866 20130101; A61K 9/4891 20130101;
A61K 9/2846 20130101; A61K 9/2866 20130101; A61K 9/2054
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/28 20060101 A61K009/28; A61K 9/48 20060101
A61K009/48 |
Claims
1. An article configured for release of a therapeutic agent in a
colon of a subject, comprising: a first portion comprising a
secretion inducing agent; a second portion adjacent the first
portion, the second portion comprising a therapeutic agent; and a
degradable coating associated with the article.
2. An article configured for release of a therapeutic agent in a
portion of an intestine of a subject, comprising: a first component
configured to increase the amount of intestinal fluid present in
the intestine of the subject; and a second component associated
with the first component configured to release a therapeutic agent
in the intestine of the subject.
3. An article of claim 2, wherein the portion of the intestine is
the colon of the subject.
4. An article of claim 1, wherein the secretion inducing agent is
configured to increase the water content in the colon of the
subject.
5. (canceled)
6. An article of claim 1, wherein the secretion inducing agent is a
bile acid or a salt thereof.
7. An article of claim 1, wherein the secretion inducing agent is
chenodeoxycholic acid or a salt thereof.
8. An article of claim 1, wherein the degradable coating comprises
Eudragit S100, Phloral, HPMC or duocaot.
9. An article of claim 1, wherein a local concentration of the
secretion inducing agent is at least 3 mM.
10. (canceled)
11. An article as in claim 1, wherein the article further comprises
hydroxypropylmethyl cellulose.
12. An article as in claim 1, wherein the article further comprises
magnesium stearate.
13. (canceled)
14. A method for administering a therapeutic agent, comprising:
administering, to a subject, an article, the article comprising a
first portion comprising a secretion inducing agent, a second
portion adjacent the first portion, the second portion comprising
the therapeutic agent, and a degradable coating associated with the
article, wherein the secretion inducing agent is configured to
increase an amount of intestinal fluid present in an intestine of
the subject; and releasing the therapeutic agent from article to
the intestine of the subject.
15. A method as in claim 14, wherein secretion inducing agent is a
bile acid or a salt thereof.
16. A method as in claim 14, wherein the secretion inducing agent
is chendeoxycholic acid or a salt thereof.
17. A method as in claim 14, wherein the secretion inducing agent
is configured to fully dissolve within one-fifth of the distance
between the ileocecal valve and the hepatic flexure.
18. A method as in claim 14, wherein a local concentration of the
secretion inducing agent is at least 3 mM.
19. (canceled)
20. A method as in claim 14, wherein the secretion inducing agent
and the therapeutic agent are introduced orally via a tablet, a
pill, or a capsule comprising the secretion inducing agent and the
therapeutic agent.
21. A method as in claim 14, wherein the secretion inducing agent
does not induce abdominal pain in the subject.
22. An article as in claim 14, wherein the secretion inducing agent
is configured to increase the motility of the gastrointestinal
tract of the subject.
23. An article as in claim 1, wherein the secretion inducing agent
is a bile acid or a salt thereof, and the therapeutic agent is a
bile acid or a salt thereof.
24. An article as in claim 1, wherein the section inducing agent is
chenodeoxycholic acid or a salt thereof, and the therapeutic agent
is a bile acid or salts thereof.
25. An article as in claim 1, wherein the amount of the
secretion-inducing agent is greater than or equal to 5 mg and less
than or equal to 5 g.
26. An article as in claim 14, wherein the amount of the
therapeutic agent present in the article is greater than or equal
to 10 mg and less than or equal to 10 g.
27. An article as in claim 1, wherein the wt % of the
secretion-inducing agent relative to the total weight of the
article is greater than or equal to 10 wt % and less than or equal
to 95 wt %.
28. An article as in claim 1, wherein a wt % of the therapeutic
agent relative to the total weight of the article is greater than
or equal to 10 wt % and less than or equal to 95 wt %.
29. An article as in claim 1, wherein a ratio of the first portion
and the second portion is greater than or equal to 1:1 and less
than or equal to 1:99.
30. (canceled)
31. An article as in claim 1, wherein a mass ratio of the
secretion-inducing agent to the therapeutic agent is greater than
or equal to 10:90 and less than or equal to 90:10.
Description
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application No. 62/885,450, filed Aug.
12, 2019, and entitled "ARTICLES AND METHODS FOR ADMINISTRATION OF
THERAPEUTIC AGENTS," which is incorporated herein by reference in
its entirety for all purposes.
TECHNICAL FIELD
[0002] Articles and methods related to administration of a
therapeutic agent to the colon of a subject are generally
described.
BACKGROUND
[0003] Local and controlled delivery of drugs to the colon persists
as a challenge in the delivery of pharmaceuticals to the
gastrointestinal tract. Novel technologies that can address this
issue stand to improve the efficacy of drugs while reducing the
likelihood of adverse effects. Accordingly, improved methods of
drug delivery to the colon are needed.
SUMMARY
[0004] The subject matter of the present invention involves, in
some cases, interrelated products, alternative solutions to a
particular problem, and/or a plurality of different uses of one or
more systems and/or articles.
[0005] In one aspect, articles configured for release of a
therapeutic agent in a colon of a subject are provided. In some
embodiments, the article comprises a first portion comprising a
secretion inducing agent, a second portion adjacent the first
portion, the second portion comprising a therapeutic agent, and a
degradable coating associated with the article.
[0006] In some embodiments, the article comprises a first component
configured to increase the amount of intestinal fluid present in
the intestine of the subject and a second component associated with
the first component configured to release a therapeutic agent in
the intestine of the subject.
[0007] In another aspect, methods are provided. In some
embodiments, the method comprises exposing a portion of an
intestine of a subject to an intestinal secretion inducing agent
such that the intestine is induced to release intestinal fluids and
providing a therapeutic agent to a portion of a intestine of the
subject, wherein the secretion inducing agent increases the amount
of the therapeutic agent available for absorption by the intestine
of the subject.
[0008] In some embodiments, the method comprises administering, to
a subject, an article, the article comprising a first portion
comprising a secretion inducing agent, a second portion adjacent
the first portion, the second portion comprising the therapeutic
agent, and a degradable coating associated with the article,
wherein the secretion inducing agent is configured to increase an
amount of intestinal fluid present in an intestine of the subject
and releasing the therapeutic agent from article to the intestine
of the subject.
[0009] Other advantages and novel features of the present invention
will become apparent from the following detailed description of
various non-limiting embodiments of the invention when considered
in conjunction with the accompanying figures. In cases where the
present specification and a document incorporated by reference
include conflicting and/or inconsistent disclosure, the present
specification shall control.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Non-limiting embodiments of the present invention will be
described by way of example with reference to the accompanying
figures, which are schematic and are not intended to be drawn to
scale. In the figures, each identical or nearly identical component
illustrated is typically represented by a single numeral. For
purposes of clarity, not every component is labeled in every
figure, nor is every component of each embodiment of the invention
shown where illustration is not necessary to allow those of
ordinary skill in the art to understand the invention. In the
figures:
[0011] FIG. 1 shows a schematic diagram of an exemplary article
configured for the controlled release of a therapeutic agent,
according to one set of embodiments;
[0012] FIG. 2 shows a schematic diagram of an exemplary article
configured for the controlled release of a therapeutic agent,
according to one set of embodiments;
[0013] FIG. 3 shows a schematic illustration of an exemplary
article moving through the gastrointestinal tract of a subject,
according to one set of embodiments;
[0014] FIG. 4 shows a plot of change in intrarectal pressure versus
time, according to one set of embodiments;
[0015] FIG. 5 shows a schematic diagram of an exemplary article,
according to one set of embodiments;
[0016] FIG. 6 shows a schematic diagram of an exemplary article,
according to one set of embodiments;
[0017] FIG. 7A shows in vitro dissolution profiles for exemplary
bilayer delivery systems, according to one set of embodiments;
[0018] FIG. 7B shows in vitro dissolution profiles for exemplary
bilayer delivery systems, according to one set of embodiments;
[0019] FIG. 8A shows exemplary bilayer delivery system before and
after release, according to one set of embodiments;
[0020] FIG. 8B shows exemplary bilayer delivery system before and
after release, according to one set of embodiments;
[0021] FIG. 9 shows a schematic illustration of an article
configured to release NaCDC as the secretion inducing agent and
5-aminosalycic acid as the therapeutic agent, according to one set
of embodiments;
[0022] FIG. 10A shows the release profile over time for a
traditional capsule and a traditional controlled release delivery
system ("single layered") versus articles described herein
("bilayer"), according to one set of embodiments;
[0023] FIG. 10B shows the release profile over time for a
traditional capsule and a traditional controlled release delivery
system ("single layered") versus articles described herein
("bilayer"), according to one set of embodiments;
[0024] FIG. 10C shows the release profile over time for a
traditional capsule and a traditional controlled release delivery
system ("single layered") versus articles described herein
("bilayer"), according to one set of embodiments;
[0025] FIG. 10D shows the release profile over time for a
traditional capsule and a traditional controlled release delivery
system ("single layered") versus articles described herein
("bilayer"), according to one set of embodiments;
[0026] FIG. 11A shows modeled colonic Na-CDC concentration
delivered as delayed bolus as described in conventional drug
delivery systems and delayed and extended release with first order
release kinetics, according to certain embodiments;
[0027] FIG. 11B shows modeled colonic Na-CDC concentration
delivered as delayed bolus as described in conventional drug
delivery systems and delayed and extended release with first order
release kinetics, according to certain embodiments;
[0028] FIG. 12A shows in vivo evaluation of CDC bilayer delivery
systems as compared to the capsule formulation using a Kaplan Meyer
plot demonstrating the bilayer delivery system's capacity to
maintain integrity throughout intestinal passage in swine and a
retrieved dissected delivery systems after 4 hours, according to
one set of embodiments;
[0029] FIG. 12B shows representative rectal manometry patterns
following rectal placement of uncoated bilayer delivery systems or
CDC capsules with amplitudes of three rectal manometry patterns and
giant contractions indicated by arrowheads (data normalized to the
mean amplitude), according to one set of embodiments;
[0030] FIG. 13A is a photographic image of bilayered delivery
systems retrieved from the small intestine of a terminal pig model
where a black arrow indicates one out of the twelve delivery
systems disintegrated after 4 hours while the rest remained intact,
according to one set of embodiments;
[0031] FIG. 13B is a photographic image of bilayered delivery
systems retrieved from the small intestine of a terminal pig model
where a black arrow indicates one out of the twelve delivery
systems disintegrated after 4 hours while the rest remained intact,
according to one set of embodiments;
[0032] FIG. 13C is a photographic image of bilayered delivery
systems retrieved from the small intestine of a terminal pig model
where a black arrow indicates one out of the twelve delivery
systems disintegrated after 4 hours while the rest remained intact,
according to one set of embodiments;
[0033] FIG. 14A shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0034] FIG. 14B shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0035] FIG. 14C shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0036] FIG. 14D shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0037] FIG. 14E shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0038] FIG. 14F shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0039] FIG. 14G shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0040] FIG. 14H shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0041] FIG. 14I shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0042] FIG. 14J shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0043] FIG. 14K shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0044] FIG. 14L shows pharmacokinetic evaluation of the bilayer
delivery system versus traditional formulations using in vitro and
in silico data, according to one set of embodiments;
[0045] FIG. 15A shows the in vitro release pattern of the bilayer
delivery system where release was assessed in Simulated Intestinal
Fluid (0.2M, SIF, pH 6.8) for one hour before the pH was adjusted
to pH 7.4 (0.2M NaOH, 100 rpm), according to one set of
embodiments; and
[0046] FIG. 15B shows the in vitro release pattern of the capsule
formulation where release was assessed in Simulated Intestinal
Fluid (0.2M, SIF, pH 6.8) for one hour before the pH was adjusted
to pH 7.4 (0.2M NaOH, 100 rpm), according to one set of
embodiments.
DETAILED DESCRIPTION
[0047] Articles and methods for delivering a therapeutic agent to a
subject are described. These articles and methods may be useful, in
some cases, for the delivery of therapeutic agents to the colon of
a subject. In some embodiments, an article is configured to release
a secretion inducing agent e.g., to stimulate the release of
intestinal fluids. The article, in some embodiments, comprises a
therapeutic agent such that the stimulated release of intestinal
fluid increases the amount of therapeutic agent available for
absorption by the colon. For example, in some embodiments, the
articles and methods described herein advantageously promote
increased absorption of therapeutic agents in subjects as compared
to traditionally administered therapeutic agents without additional
components such as a secretion inducing agent. In some embodiments,
articles and methods described herein may increase the motility of
the colon of a subject. The increase in contractions and movement
of fluidic in the colon caused by increase motility may
advantageously facilitate the dissolution or absorption of the
therapeutic agent.
[0048] In one aspect, an article is described that is configured to
release a therapeutic agent to the colon of a subject. The article
may have a first portion comprising a secretion inducing agent, a
second portion comprising a therapeutic agent, and a degradable
coating associated with the article. In some embodiments, the
article is absent a coating. In some embodiments, the article is a
pill, a tablet, or a capsule, which may be administered orally to a
subject.
[0049] In another aspect, an article is described that is
configured for release of a therapeutic agent in a portion of an
intestine of a subject. The article may comprise a first component
configured to increase the amount of intestinal fluid present in
the intestine of a subject and a second component associated with
the first component configured to release a therapeutic agent in
the intestine of the subject.
[0050] In yet another aspect, a method is described for intestinal
drug delivery. The method comprises exposing a portion of an
intestine to an intestinal secretion inducing agent such that the
intestine is induced to release intestinal fluid. The method may
also comprise providing a therapeutic agent to a portion of the
intestine wherein the secretion inducing agent increases the amount
of therapeutic agent available for absorption by the intestine of
the subject.
[0051] In yet another aspect still, a method of administering a
therapeutic agent is described. The method may comprise
administering an article to a subject where the article may
comprise a secretion inducing agent, a second portion adjacent to
the first portion, the second portion comprising the therapeutic
agent, and a degradable coating associated with the article. The
secretion inducing agent may be configured to increase an amount of
intestinal fluid present in the intestine and the method may
involve releasing a therapeutic agent from the article to the
intestine of the subject.
[0052] Certain embodiments of the article have an associated
degradable coating. In some embodiments, and without wishing to be
bound by theory, the degradable coating enables tuning of a release
location along the intestinal tract of the subject where the
secretion inducing agent and the therapeutic agent is released. In
some embodiments, the stimulated release of the intestinal fluids
by the secretion inducing agent enhances the local solubility of
the therapeutic agent along the colon.
[0053] A "subject", as used herein, refers to any animal such as a
mammal (e.g., a human). Non-limiting examples of subjects include a
human, a non-human primate, a cow, a horse, a pig, a sheep, a goat,
a dog, a cat or a rodent such as a mouse, a rat, a hamster, a bird,
a fish, or a guinea pig. The embodiments described herein may be,
in some cases, directed toward use with humans. In some
embodiments, a subject may demonstrate health benefits, e.g., upon
administration of the articles described herein.
[0054] Certain embodiments of the invention advantageously provide
for the enhanced solubility of a therapeutic agent in the colon. In
embodiments where the article is configured with a coating, the
coating mat be advantageously be configured such that the secretion
inducing agent is released in desired locations of the colon (e.g.,
as opposed to other undesired and/or less effective portions of the
digestive tract). In certain cases, the coating is configured to
prevent (e.g., substantially inhibit) the release of the secretion
inducing agent in a location along the gastrointestinal (GI) tract
in a manner that may cause abdominal pain to the subject (for
example, the coating may prevent the burst release of a secretion
inducing agent).
[0055] In one set of embodiments, the secretion inducing agent is a
bile acid, such a chenodeoxycholic acid (CDC). In some embodiments,
when configured with a suitable coating, for example, Eudragit
S100, articles described herein advantageously do not substantially
release the secretion inducing agent or the therapeutic agent until
reaching a desired location for release (e.g., distal part of the
ileum). In some embodiments, upon reaching the desired location,
the degradable coating releases the secretion inducing agent to
produce a local internal concentration of the secretion inducing
agent e.g., of at least 3 mM or at least 5 mM at a location
internal to the subject. Without wishing to be bound by theory, a
local increase in the concentration of secretion inducing agents
may, in some cases, stimulate the release of (additional)
intestinal fluids, thereby enhancing the solubility of a desired
therapeutic agent (e.g., the therapeutic agent of the article
described herein). In certain embodiments, the secretion inducing
agent may also increase the motility of the colon to advantageously
enhance the dissolution and/or absorption of the therapeutic agent.
In some embodiments, this therapeutic agent may be a bile acid or a
salt thereof, such as sodium chenodeoxycholate (NaCDC).
[0056] In some embodiments, the article comprises a first portion,
comprising a secretion inducing agent, adjacent a second portion,
comprising a therapeutic agent. As used herein, when a portion or
layer is referred to as being "adjacent," it may be directly
adjacent to another component or portion, or one or more
intervening components (e.g., portions including, but not limited
to portions comprising a therapeutic agent and portions comprising
a secretion inducing agent) also may be present. A portion or layer
that is "directly adjacent" to another portion/layer means that no
intervening component is present.
[0057] FIG. 1 shows a non-limiting example of an article configured
for delivery of a therapeutic agent. In some embodiments, article
100 has a first portion 110 (e.g., comprising a secretion inducing
agent) and a second portion 115 (e.g., comprising a therapeutic
agent) adjacent to first portion 110. In some embodiments, a
coating 120 may be associated with article 100. In some
embodiments, coating 120 may be configured to protect (e.g., from
dissolution) first portion 110 and/or second portion 115 until
reaching a desired location internal to the subject. In some
embodiments, first portion 110 is a first layer and second portion
120 is a second layer in article 100. While first portion 110 and
second portion 120 are depicted in FIG. 1, one or more additional
portions and/or layers may also be present in article 100.
[0058] While FIG. 1 is shown as coating 120 surrounding article
100, in some embodiments, coating 120 may only partially surround
article 100, or coating 120 may be absent. In some embodiments,
first portion 110 and second portion 115 may be in direct contact
as depicted in FIG. 1. In some embodiments, first portion 110 and
second portion 115 may be spatially separated (e.g., one or more
layers and/or components may be positioned between first portion
110 and second portion 115). In certain embodiments, first portion
110 and the second portion 115 may be encapsulated in distinct or
overlapping portions of coating 120.
[0059] In another embodiment, referring now to FIG. 2, a
non-limiting schematic example of an article configured for
delivery of a therapeutic agent is shown. Article 200 comprises a
first portion 210 (e.g., comprising a secretion inducing agent) and
a second portion 215 (e.g., comprising a therapeutic agent)
adjacent first portion 210. In some embodiments, a coating 220 may
be associated with second portion 215, as depicted in FIG. 2. In
some embodiments, a coating may be associated with first portion
210 (e.g., at least partially encapsulating first portion 210,
fully encapsulating first portion 210). In some embodiments,
coating 220 may be configured to protect (e.g., from dissolution)
second portion 215 but dissolve before first portion 210. In some
embodiments, first portion 210 may surround second portion 215 and
coating 215 prior to administration to a subject. While first
portion 210 and second portion 220 are depicted in FIG. 2, one or
more additional portions and/or coatings may also be present in
article 200.
[0060] While FIG. 2 is shown as coating 220 surrounding second
portion 215, some embodiments of articles described may have
coating 220 only partially surrounding second portion 215 or
coating 220 may be absent. In some embodiments, first portion 210
and second portion 215 may be in direct contact without a coating.
In some embodiments, first portion 210 and second portion 215 may
be spatially separated (e.g., one or more portions and/or
components may be positioned between first portion 210 and second
portion 215).
[0061] In some embodiments, a ratio of the first portion (e.g.,
comprising a secretion-inducing agent) and the second portion
(e.g., comprising a therapeutic agent) is greater than or equal to
1:1, greater than or equal to 1:2, greater than or equal to 1:3,
greater than or equal to 1:4, greater than or equal to 1:5; greater
than or equal to 1:10, greater than or equal to 1:20, greater than
or equal to 1:30, greater than or equal to 1:40, greater than or
equal to 1:50, greater than or equal to 1:60, greater than or equal
to 1:70, greater than or equal to 1:75, greater than or equal to
1:80, greater than or equal to 1:85, greater than or equal to 1:90,
greater than or equal to 1:95, greater than or equal to 1:96,
greater than or equal to 1:97, greater than or equal to 1:98, or
greater than or equal to 1:99. In some embodiments, a ratio of the
first portion to the second portion is less than or equal to 1:99,
less than or equal to 1:98, less than or equal to 1:97, less than
or equal to 1:96, less than or equal to 1:95, less than or equal to
1:90, less than or equal to 1:85, less than or equal to 1:80, less
than or equal to 1:75, less than or equal to 1:70, less than or
equal to 1:60, less than or equal to 1:50, less than or equal to
1:40, less than or equal to 1:30, less than or equal to 1:20, less
than or equal to 1:10, less than or equal to 1:5, less than or
equal to 1:4, less than or equal to 1:3, less than or equal to 1:2,
or less than or equal to 1:1. Combinations of the above-referenced
ranges are also possible (e.g., greater than or equal to 1:1 and
less than or equal to 1:99). Other ranges are possible. Selecting a
particular ratio of the first portion (e.g., comprising the
secretion-inducing agent) and the second portion (e.g., comprising
the therapeutic agent) can advantageously control the release of
the therapeutic agent. Those skilled in the art based on the
teachings of the present disclosure will be capable of selection an
appropriate ratio of the first portion and the second portion.
[0062] In some embodiments, a ratio of the second portion (e.g.,
comprising a therapeutic agent) and the first portion (e.g.,
comprising a secretion-inducing agent) is greater than or equal to
1:1, greater than or equal to 1:2, greater than or equal to 1:3,
greater than or equal to 1:4, greater than or equal to 1:5; greater
than or equal to 1:10, greater than or equal to 1:20, greater than
or equal to 1:30, greater than or equal to 1:40, greater than or
equal to 1:50, greater than or equal to 1:60, greater than or equal
to 1:70, greater than or equal to 1:75, greater than or equal to
1:80, greater than or equal to 1:85, greater than or equal to 1:90,
greater than or equal to 1:95, greater than or equal to 1:96,
greater than or equal to 1:97, greater than or equal to 1:98, or
greater than or equal to 1:99. In some embodiments, a ratio of the
second portion to the first portion is less than or equal to 1:99,
less than or equal to 1: 198, less than or equal to 1:97, less than
or equal to 1:96, less than or equal to 1:95, less than or equal to
1:90, less than or equal to 1:85, less than or equal to 1:80, less
than or equal to 1:75, less than or equal to 1:70, less than or
equal to 1:60, less than or equal to 1:50, less than or equal to
1:40, less than or equal to 1:30, less than or equal to 1:20, less
than or equal to 1:10, less than or equal to 1:5, less than or
equal to 1:4, less than or equal to 1:3, less than or equal to 1:2,
or less than or equal to 1:1. Combinations of the above-referenced
ranges are also possible (e.g., greater than or equal to 1:1 and
less than or equal to 1:99). Other ranges are possible.
[0063] In some embodiments, an article (e.g. a tablet comprising a
secretion inducing agent and a therapeutic agent) may be
administered to a subject orally where, in some cases, it travels
through the gastrointestinal tract of the subject until reaching a
desired internal location. For example, as illustrated
schematically in FIG. 3, an article configured for release of a
therapeutic agent may be administered to a subject (e.g., orally)
such it enters the gastrointestinal tract of the subject. In some
embodiments, upon reaching the colon of the subject, the coating at
least partially degrade to expose a first portion comprising a
secretion inducting agent. The secretion inducing agent stimulates
the release of additional intestinal fluids. The second portion
comprising a therapeutic agent, in some embodiments, dissolves such
that the therapeutic agent is released at a location internal to
the subject. In some embodiments, advantageously, the release of
additional intestinal fluids may also help to improve the
dissolution and/or solubility of the therapeutic agent and/or
enhance the amount absorbed by the colon.
[0064] In some embodiments, a secretion inducing agent may be
provided. As used herein, a secretion inducing agent generally
refers to a chemical species that stimulates the release of
increased intestinal fluid along the gastrointestinal tract (e.g.,
relative to the basal release of intestinal fluid and/or the basal
release of intestinal fluid in response to a foreign body present
in the gastrointestinal tract such as food). In this way, the
increased amount of intestinal fluid present enhances the
solubility and/or the absorption of a therapeutic agent. In some
embodiments, the secretion inducing agent is a bile acid or a salt
thereof. In some embodiments, the bile acid is chendeoxycholic
acid. In certain embodiments, this secretion inducing agent is a
salt of chendeoxycholic acid, e.g., sodium chendeoxycholate
(NaCDC). In some embodiments, the secretion inducing agent
comprises bisacodyl, senna, sennoside, linaclotide, plecanatide,
lubiprostone, methylnaltrexone, naloxegol, polyethyleneglycole,
lactulose, or prucalopride. In some embodiments, the secretion
inducing agent may be a salt, such as magnesium citrate, magnesium
hydroxide, or a bile salt, as non-limiting examples. Other
secretion inducing agents are possible, as any chemical species
that stimulates the release of intestinal fluid along the
gastrointestinal tract may be function as a secretion inducing
agent.
[0065] In some embodiments, the wt % of the secretion-inducing
agent relative to the total weight of the article (e.g., a tablet,
a capsule) is greater than or equal to 10 wt %, greater than or
equal to 15 wt %, greater than or equal to 20 wt %, greater than or
equal to 25 wt %, greater than or equal to 30 wt %, greater than or
equal 40 wt %, greater than or equal to 50 wt %, greater than or
equal to 60 wt %, greater than or equal to 70 wt %, greater than or
equal to 75 wt % , greater than or equal to 80 wt %, greater than
or equal 90 wt %, or greater than or equal to 95 wt %. In some
embodiments, the wt % of the secretion-inducing agent relative to
the total weight of the article is less than or equal to 95 wt %,
less than or equal to 90 wt %, less than or equal to 80 wt %, less
than or equal to 75 wt %, less than or equal to 70 wt %, less than
or equal to 60 wt %, less than or equal to 50 wt %, less than or
equal to 40 wt %, less than or equal to 30 wt %, less than or equal
to 25 wt %, less than or equal to 20 wt %, less than or equal to 15
wt %, or less than or equal to 10 wt %. Combinations of the
above-references ranges are also possible (e.g., greater than or
equal to 10 wt % and less than or equal to 50 wt %). Other ranges
are possible.
[0066] In some embodiments, the amount (e.g., the mass) of the
secretion-inducing agent present in the article (e.g., in a
capsule, in a tablet) is greater than or equal to 5 mg, greater
than or equal to 10 mg, greater than or equal to 20 mg, greater
than or equal to 25 mg, greater than or equal to 30 mg, greater
than or equal to 50 mg, greater than or equal to 60 mg, greater
than or equal to 70 mg, greater than or equal to 75 mg, greater
than or equal to 80 mg, greater than or equal to 90 mg, greater
than or equal to 95 mg, greater than or equal to 100 mg, greater
than or equal to 250 mg, greater than or equal to 500 mg, greater
than or equal to 750 mg, greater than or equal to 1 g, greater than
or equal to 2 g, greater than or equal to 3 g, greater than or
equal to 4 g, or greater than or equal to 5 g. In some embodiments,
the amount of the secretion-inducing agent is less than or equal to
5 g, less than or equal to 4 g, less than or equal to 3 g, less
than or equal to 2 g, less than or equal to 1 g, less than or equal
to 750 mg, less than or equal to 500 mg, less than or equal to 250
mg, less than or equal to 100 mg, less than or equal to 95 mg, less
than or equal to 90 mg, less than or equal 80 mg, less than or
equal to 75 mg, less than or equal to 70 mg, less than or equal to
60 mg, less than or equal to 50 mg, less than or equal to 40 mg,
less than or equal to 30 mg, less than or equal to 25 mg, less than
or equal to 20 mg, less than or equal to 10 mg, or less than or
equal to 5 mg. Combinations of the above-referenced ranges are also
possible (e.g., greater than or equal to 5 mg and less than or
equal to 5 g). Other ranges are possible.
[0067] Certain embodiments comprise a therapeutic agent associated
with the article, as described herein. According to some
embodiments, the therapeutic agent may be one or a combination of
therapeutic, diagnostic, and/or enhancement agents, such as drugs,
nutrients, microorganisms, in vivo sensors, and tracers. In some
embodiments, the therapeutic agent is a nutraceutical, prophylactic
or diagnostic agent. While much of the specification describes the
use of therapeutic agents, other agents listed herein are also
possible. Agents can include, but are not limited to, any synthetic
or naturally-occurring biologically active compound or composition
of matter which, when administered to a subject (e.g., a human or
nonhuman animal), induces a desired pharmacologic, immunogenic,
and/or physiologic effect by local and/or systemic action, such as
increasing the amount of intestinal fluid present in the colon of a
subject. For example, useful or potentially useful within the
context of certain embodiments are compounds or chemicals
traditionally regarded as drugs, vaccines, and biopharmaceuticals.
Certain such agents may include molecules such as proteins,
peptides, hormones, nucleic acids, gene constructs, etc., for use
in therapeutic, diagnostic, and/or enhancement areas, including,
but not limited to medical or veterinary treatment, prevention,
diagnosis, and/or mitigation of disease or illness (e.g., HMG-CoA
reductase inhibitors (statins) like rosuvastatin, nonsteroidal
anti-inflammatory drugs like meloxicam, selective serotonin
reuptake inhibitors like escitalopram, blood thinning agents like
clopidogrel, steroids like prednisone, antipsychotics like
aripiprazole and risperidone, analgesics like buprenorphine,
antagonists like naloxone, montelukast, and memantine, cardiac
glycosides like digoxin, alpha blockers like tamsulosin,
cholesterol absorption inhibitors like ezetimibe, metabolites like
colchicine, antihistamines like loratadine and cetirizine, opioids
like loperamide, proton-pump inhibitors like omeprazole,
anti(retro)viral agents like entecavir, dolutegravir, rilpivirine,
and cabotegravir, antibiotics like doxycycline, ciprofloxacin, and
azithromycin, anti-malarial agents, and synthroid/levothyroxine);
substance abuse treatment (e.g., methadone and varenicline); family
planning (e.g., hormonal contraception); performance enhancement
(e.g., stimulants like caffeine); and nutrition and supplements
(e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine,
niacin, vitamin C, vitamin D, and other vitamin or mineral
supplements).
[0068] In certain embodiments, the therapeutic agent is one or more
specific therapeutic agents. As used herein, the term "therapeutic
agent" (or also referred to as a "drug") refers to an agent that is
administered to a subject to treat a disease, disorder, or other
clinically recognized condition, or for prophylactic purposes, and
has a clinically significant effect on the body of the subject to
treat and/or prevent the disease, disorder, or condition. Listings
of examples of known therapeutic agents can be found, for example,
in the United States Pharmacopeia (USP), Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001;
Katzung, B. (ed.) Basic and Clinical Pharmacology,
McGraw-Hill/Appleton & Lange; 8th edition (Sep. 21, 2000);
Physician's Desk Reference (Thomson Publishing), and/or The Merck
Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed
(2006) following its publication, Mark H. Beers and Robert Berkow
(eds.), Merck Publishing Group, or, in the case of animals, The
Merck Veterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck
Publishing Group, 2005; and "Approved Drug Products with
Therapeutic Equivalence and Evaluations," published by the United
States Food and Drug Administration (F.D.A.) (the "Orange Book").
Examples of drugs approved for human use are listed by the FDA
under 21 C.F.R. .sctn..sctn. 330.5, 331 through 361, and 440
through 460, incorporated herein by reference; drugs for veterinary
use are listed by the FDA under 21 C.F.R. .sctn..sctn. 500 through
589, incorporated herein by reference. In certain embodiments, the
therapeutic agent is a small molecule. Exemplary classes of
therapeutic agents include, but are not limited to, analgesics,
anti-analgesics, anti-inflammatory drugs, antipyretics,
antidepressants, antiepileptics, antipsychotic agents,
neuroprotective agents, anti-proliferatives, such as anti-cancer
agents, antihistamines, antimigraine drugs, hormones,
prostaglandins, antimicrobials (including antibiotics, antifungals,
antivirals, antiparasitics), antimuscarinics, anxioltyics, bacterio
statics, immunosuppressant agents, sedatives, hypnotics,
antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular
drugs, anesthetics, anti-coagulants, inhibitors of an enzyme,
steroidal agents, steroidal or non-steroidal anti-inflammatory
agents, corticosteroids, dopaminergics, electrolytes,
gastro-intestinal drugs, muscle relaxants, nutritional agents,
vitamins, parasympathomimetics, stimulants, anorectics and
anti-narcoleptics. Nutraceuticals can also be incorporated into the
drug delivery device. These may be vitamins, supplements such as
calcium or biotin, or natural ingredients such as plant extracts or
phytohormones.
[0069] In another embodiment, the therapeutic agent is an
immunosuppressive agent. Exemplary immunosuppressive agents include
glucocorticoids, cytostatics (such as alkylating agents,
antimetabolites, and cytotoxic antibodies), antibodies (such as
those directed against T-cell recepotors or 11-2 receptors), drugs
acting on immunophilins (such as cyclosporine, tacrolimus, and
sirolimus) and other drugs (such as interferons, opioids, TNF
binding proteins, mycophenolate, and other small molecules such as
fingolimod).
[0070] In certain embodiments, the therapeutic agent is a hormone
or derivative thereof. Non-limiting examples of hormones include
insulin, growth hormone (e.g., human growth hormone), vasopressin,
melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein
hormones (e.g., luteinzing hormone, follicle-stimulating hormone,
thyroid-stimulating hormone), eicosanoids, estrogen, progestin,
testosterone, estradiol, cortisol, adrenaline, and other
steroids.
[0071] In some embodiments, the therapeutic agent is a bile acid.
Bile acids are understood by those skilled in the art as steroid
acids predominately in the bile of mammals (e.g. humans) and other
vertebrates. For certain embodiments, the bile acid is in the form
of a bile salt, i.e., the conjugate base of the bile acid and an
appropriate cation (e.g. sodium, potassium, etc.). In certain
embodiments, the bile salt is sodium chenodeoxycholic acid.
Non-limiting examples of the bile acids (or salts thereof) include
chenodeoxycholic acid, deoxycholic acid, taurocholic, glycocholic
acid, choic acid, taurochenodeoxycholic acid, glycochenodeoxycholic
acid, deoxycholic acid, and lithocholic acid. Other bile acids (and
salts thereof) are possible as the disclosure is not so limited.
While some bile acids have been used to attempt to treat
conditions, such as irritable bowel syndrome with constipation,
these attempts were associated with a high frequency of abdominal
pain. However, the Inventors have recognized and appreciated that a
controlled release using a bi-layered delivery system consisting of
an immediate release layer and a controlled release layer could
improve the frequency of abdominal pain, exemplified with a
reduction in abdominal contractions of the subject. Without wishing
to be bound by any theory, after disintegration of the bile acid,
the local `super-physiological` concentrations can trigger adverse
effects in the proximal colon. Super-physiological bile acid
concentrations have previously been linked to giant contractions
and inflammation in the GI tract. While conventional colonic drug
delivery systems, like the single layered release system, used as a
control in some examples, can impair drug dissolution and
solubility. However, it has been recognized and appreciated within
the context of this disclosure that bilayered delivery system that
first achieve a prosecretory local concentration of CDC (e.g.,
.about.5 mM) can facilitate controlled release along the colon from
a second layer.
[0072] In some embodiments, the therapeutic agent is a small
molecule drug having molecular weight less than about 2500 Daltons,
less than about 2000 Daltons, less than about 1500 Daltons, less
than about 1000 Daltons, less than about 750 Daltons, less than
about 500 Daltons, less or than about 400 Daltons. In some cases,
the therapeutic agent is a small molecule drug having molecular
weight between 200 Daltons and 400 Daltons, between 400 Daltons and
1000 Daltons, or between 500 Daltons and 2500 Daltons.
[0073] In some embodiments, the therapeutic agent is selected from
the group consisting of active pharmaceutical agents such as bile
acids, probiotics, polysaccharides (e.g. Reglemers.TM.), compounds
derived from fecal matter, glycans, antigen mimics, Cas nucleases,
nucleic acids, peptides, proteins, bacteriophage, modified
bacteria, DNA, mRNA, human growth hormone, monoclonal antibodies,
adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide,
liraglutide, dulaglitide, exenatide, factor VIII, small molecule
drugs, progrstin, vaccines, subunit vaccines, recombinant vaccines,
polysaccharide vaccines, and conjugate vaccines, toxoid vaccines,
influenza vaccine, shingles vaccine, prevnar pneumonia vaccine, MMR
vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4 env
Clade C, HIV vaccine Ad4-mGag, DNA vaccines, RNA vaccines,
etanercept, infliximab, filgastrim, glatiramer acetate, rituximab,
bevacizumab, any molecule encapsulated in a nanoparticle,
epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other
enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab,
brodalumab, guselkumab, secikinumab, omalizumab, TNF-alpha
inhibitors, interleukin inhibitors, vedolizumab, octreotide,
teriperatide, CRISPR-Cas9, antisense oligonucleotides, and
ondansetron. In certain embodiments, the therapeutic agent may
comprise a polyunsaturated fatty acid (e.g. butyric acid, propionic
acid), an omega-3 fatty acid (e.g., docosahexaenoic acid,
eicosapentaenoic acid), a bismuth salt e.g. (bismuth subgallate),
or a polysaccharide.
[0074] Certain embodiments may comprise a therapeutic system.
Non-limiting examples of therapeutic systems include , Lialda.RTM.,
Mezavant.RTM., Mesavanc .RTM., Zacol NMX.RTM., UCERIS.RTM.,
Rifamycin SV MMX.RTM., Methylene Blue MMX.RTM., Pentasa.RTM., PLGA
nanoparticles, liposomes, EUDRATEC.RTM. COL, and
self-microemulsifying drug delivery system (SMEDDS). Other
therapeutic systems may be possible.
[0075] In some embodiments, the wt % of the therapeutic agent
relative to the total weight of the article (e.g., a tablet, a
capsule) is greater than or equal to 10 wt %, greater than or equal
to 15 wt %, greater than or equal to 20 wt %, greater than or equal
to 25 wt %, greater than or equal to 30 wt %, greater than or equal
40 wt %, greater than or equal to 50 wt %, greater than or equal to
60 wt %, greater than or equal to 70 wt %, greater than or equal to
75 wt % , greater than or equal to 80 wt %, greater than or equal
90 wt %, or greater than or equal to 95 wt %. In some embodiments,
the wt % of therapeutic agent relative to the total weight of the
article is less than or equal to 95 wt %, less than or equal to 90
wt %, less than or equal to 80 wt %, less than or equal to 75 wt %,
less than or equal to 70 wt %, less than or equal to 60 wt %, less
than or equal to 50 wt %, less than or equal to 40 wt %, less than
or equal to 30 wt %, less than or equal to 25 wt %, less than or
equal to 20 wt %, less than or equal to 15 wt %, or less than or
equal to 10 wt %. Combinations of the above-references ranges are
also possible (e.g., greater than or equal to 10 wt % and less than
or equal to 50 wt %). Other ranges are possible.
[0076] In some embodiments, the amount (e.g., the mass) of the
therapeutic agent present in the article (e.g., in a capsule, in a
tablet) is greater than or equal to 10 mg, greater than or equal to
20 mg, greater than or equal to 25 mg, greater than or equal to 30
mg, greater than or equal to 50 mg, greater than or equal to 60 mg,
greater than or equal to 70 mg, greater than or equal to 75 mg,
greater than or equal to 80 mg, greater than or equal to 90 mg,
greater than or equal to 95 mg, greater than or equal to 100 mg,
greater than or equal to 250 mg, greater than or equal to 500 mg,
greater than or equal to 750 mg, greater than or equal to 1 g,
greater than or equal to 2 g, greater than or equal to 3 g, greater
than or equal to 4 g, greater than or equal to 5 g, greater than or
equal to 6 g, greater than or equal to 7 g, greater than or equal
to 8 g, greater than or equal to 9 g, or greater than or equal to
10 g. In some embodiments, the amount of the secretion-inducing
agent is less than or equal to 10 g, less than or equal to 9 g,
less than or equal to 8 g, less than or equal to 7 g, less than or
equal to 6 g, less than or equal to 5 g, less than or equal to 4 g,
less than or equal to 3 g, less than or equal to 2 g, less than or
equal to 1 g, less than or equal to 750 mg, less than or equal to
500 mg, less than or equal to 250 mg, less than or equal to 100 mg,
less than or equal to 95 mg, less than or equal to 90 mg, less than
or equal 80 mg, less than or equal to 75 mg, less than or equal to
70 mg, less than or equal to 60 mg, less than or equal to 50 mg,
less than or equal to 40 mg, less than or equal to 30 mg, less than
or equal to 25 mg, less than or equal to 20 mg, or less than or
equal to 10 mg. Combinations of the above-referenced ranges are
also possible (e.g., greater than or equal to 10 mg and less than
or equal to 10 g). Other ranges are possible.
[0077] In some embodiments, a mass ratio of a secretion-inducing
agent to a therapeutic agent is greater than or equal to 10:90,
greater than or equal to 20:80, greater than or equal to 30:70,
greater than or equal to 40:60, greater than or equal to 50:50,
greater than or equal to 60:40, greater than or equal to 70:30,
greater than or equal to 80:20, or greater than or equal to 90:10.
In some embodiments, a mass ratio of a secretion-inducing agent to
a therapeutic agent is less than or equal to 90:10, less than or
equal to 80:20, less than or equal to 70:30, less than or equal to
60:40, less than or equal to 50:50, less than or equal to 40:60,
less than or equal to 30:70, less than or equal to 20:80, or less
than or equal to 10:90. Combinations of the above-referenced ranges
are also possible (e.g., greater than or equal to 10:90 and less
than or equal to 30:70). Other ranges are possible.
[0078] In some embodiments, a coating may be associated with the
article. In certain embodiments, the coating is degradable and/or
erodible (e.g., by gastrointestinal fluids under physiological
conditions). In an exemplary set of embodiments, the degradable
coating comprises Eudragit S100. Any suitable coating that is
configured to release the secretion inducing agent to the desired
portion of the gastrointestinal tract (such as in the distal
portion of ileum or the distal part of the colon, as a non-limiting
example) may be used. Non-limiting examples of suitable degradable
coatings include Eudragit S, Phloral, CODES, and Duocoat. In some
embodiments, the coating is a erodible coating and comprises, for
example, hydroxypropylmethyl cellulose (HPMC). Other erodible
coatings are also possible.
[0079] Some embodiments of articles described herein may comprise
additional components (e.g., excipients, coatings). In some
embodiments, the additional component(s) may be unrelated to
secretion production or therapeutic abilities. The additional
components may. in some cases, help with stability of the article
(e.g. a tablet, capsule, etc.), solubility of the article, and/or
enhance the article's ability to deliver the therapeutic agent to
the desired portion of the gastrointestinal tract (e.g. as a
degradable and/or erodible coating). In some embodiments, the
additional component comprises magnesium stearate. In some
embodiments, the additional component comprises hydroxypropylmethyl
cellulose. In some embodiments, the additional component comprises
Aerosil.RTM. 200 Pharma
[0080] For some embodiments, additional components (e.g.,
excipients) may assist with forming a matrix (i.e., a surrounding
material designed to hold the components of the article together,
e.g., hold the components of an article into a tablet) around or
within the article. In some embodiments, additional components may
help control the release of components. Non-limiting examples of
suitable matrix forming and/or release controlling agents include
methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, alginates, plant derived gums,
chitosan, gelatin, pectin, carraganes, polyacrylates,
polyethyleneoxides, and starch. Examples of hydrophobic matrix
forming and/or release controlling agents include waxes, fatty
acids, fatty alcohols and esters, glycerolesters, polyesteramide,
ethylcellulose, polyethylene, polypropylene, polythiourethane,
polyvinylbutyral, polylacticacid, poly(lactide-co-glycolide),
celluloseacetate, and celluloseacetate butyrate. Other additional
components that may assist with delivery of a secretion inducing or
a therapeutic agent are also possible.
[0081] In some embodiments, the first portion, the second portion,
and/or the additional component may comprise a hydrophilising
agent. Non-limiting examples of suitable hydrophilising agents
include cyclodextrins, surfactants, solid buffers (e.g. sodium
citrate/citric acid). Other examples of hydrophilising agents are
possible as the disclosure is not so limited.
[0082] Some embodiments may improve or enhance the motility of the
gastrointestinal tract. As described herein, motility refers to the
contraction of the muscles that mix and propel contents in the
gastrointestinal (GI) tract. In some embodiments, the secretion
inducing agent, such as a bile acid, may increase the motility of
the colon, in addition to increasing gastrointestinal secretions.
Increased motility of the colon may result in improved mixing of
the therapeutic agent and hence may improve the dissolution and/or
the absorption of the therapeutic agent.
[0083] Articles described herein may be configured into any form
appropriate for administering the article to the gastrointestinal
tract. In some embodiments, the article is configured into a
tablet, a pill, or a capsule. In some embodiments, a degradable
coating is associated with the article. Other forms of the article
may be appropriate for administering to the gastrointestinal tract
as the disclosure is not so limited.
[0084] In some embodiments, the methods and articles are
administered to a subject (e.g., orally). In certain embodiments,
the system may be administered orally, rectally, vaginally,
nasally, or uretherally. In certain embodiments, upon reaching a
location internal to the subject (e.g., the gastrointestinal
tract), at least a portion of a coating degrades such that a
secretion inducing agent makes contact with a tissue located
internal to the subject. In some embodiments, contact with a tissue
stimulates the release of intestinal fluids. In some embodiments,
the location internally of the subject is the colon, the duodenum,
the ileum, the jejunum, the stomach, or the esophagus. As described
above and herein, in some embodiments, a therapeutic agent may be
released during and/or after penetration of the tissue located
internal to the subject. In some embodiments, the secretion
inducing agent promotes secretion only in desired portions along
the gastrointestinal tract, such as only along the caecum or other
parts of the ascending colon, as non-limiting examples. In some
such embodiments, such targeted secretion may advantageously
transiently initiate the release of the therapeutic agent, rather
than along the entire gastrointestinal tract. In some embodiments,
release of the therapeutic agent may be selectively released along
only desired portions of the GI tract or the colon.
[0085] In certain embodiments, articles and methods are
administered in the gastrointestinal tract. For example, in some
embodiments, a secretion inducing agent and/or a therapeutic agent
are configured to be released in a colon of a subject. In some
cases, the secretion inducing agent is released within one-fifth of
the distance between the ileocecal valve and the hepatic flexure.
Other areas along the gastrointestinal tract are also possible as
the disclosure is not intended to be so limiting.
[0086] Some embodiments are configured to release a secretion
inducing agent to the gastrointestinal tract. The secretion
inducing agent, in some embodiments, stimulates the release of
additional intestinal fluids (e.g. water, enzymes, hormones,
proteins etc.) such that there is more intestinal fluid present
with the secretion inducing agent present compared to with the
absence of a secretion inducing agent. As described herein,
intestinal fluid describes the clear to pale yellow watery
secretions from the glands lining the colon. The additional
secretions caused by the secretion inducing agent may enhance the
solubility or availability of a therapeutic agent so that it may be
better utilized by a subject. In some embodiments, the additional
secretions released as a result of the secretion inducing agent may
contain more water relative to secretions induced in the proximal
portions of the GI tract. In some such embodiments, this may
advantageously enhance the dissolution and/or the solubility of the
therapeutic agent. In some embodiments, the additional secretions
released as a result of the secretion inducing agent may contain
less digestive enzymes relative to secretions induced in the
proximal portions of the GI tract. This may advantageously allow
for a therapeutic agent that might normally degrade due to
digestive enzymes in the proximal GI tract to persist longer along
the GI tract and provide a therapeutic effect further along the GI
tract. In some embodiments, the release of additional intestinal
fluids may promote the release of more secretion inducing agent,
such that a positive feedback loop is provided. For example,
without wishing to be bound by theory, in some cases the secretion
inducing agent may promote the release of intestinal fluids, which
may in turn promote the release of additional secretion inducing
agent, which may then promote the release of more intestinal fluids
(e.g., as compared to the release of intestinal fluids without the
secretion inducing agent).
[0087] For certain embodiments, the secretion inducing agent may be
present along the gastrointestinal tract with a local concentration
of at least 3 mM. In some embodiments, the local concentration of
the secretion inducing agent is at least 5 mM. That is to say, in
some embodiments, the degradable coating releases the secretion
inducing agent to produce a local internal concentration of the
secretion inducing agent e.g., of at least 3 mM or at least 5 mM at
a location internal to the subject. In some embodiments, the
secretion inducing agent is released such that a local internal
concentration of at least 3 mM, at least 5 mM, at least 10 mM, at
least 15 mM, at least 20 mM, at least 30 mM, or at least 50 mM is
produced. In some embodiments, the secretion inducing agent is
released such that a local internal concentration of less than or
equal to 100 mM, less than or equal to 50 mM, less than or equal to
30 mM, less than or equal to20 mM, less than or equal to 15 mM,
less than or equal to 10 mM, or less than or equal to 5 mM is
produced. As described herein, "local concentration" refers to the
amount of substance per unit volume at a position nearby the
article. For example, the concentration of the secretion inducing
agent along the entirety of the gastrointestinal tract may be
substantially less than 3 mM, but the concentration of the
secretion inducing agent in the vicinity of an article configured
to release the secretion inducing agent may be equal to or greater
than 3 mM.
[0088] Certain embodiments of the article are configured into a
form suitable for administering orally to a subject, such as a
pill, a tablet, or a capsule. In some embodiments, the size of the
article may conform (e.g., fit within) with standard capsule sizes
known in the art, such as 000, 00, 0, 1, 2, 3, or 4.
[0089] In certain embodiments, an article configured for release of
a therapeutic agent may have a largest cross-sectional dimension
(e.g. a diameter) of at least 10 mm, at least 12 mm, at least 14
mm, of at least 15 mm, of at least 18 mm, of at least 19 mm, of at
least 21 mm, of at least 23 mm, or of at least 26. In some
embodiments, an article configured for release of a therapeutic
agent may have a largest cross-sectional dimension of at most 27
mm, of at most 24 mm, of at most 22 mm, of at most 20 mm, of at
most 18 mm, of at most 16 mm, of at most 15 mm, or of at most 10
mm.
[0090] Some embodiments may be configured to eliminated, reduce, or
minimize abdominal pain and/or other adverse effects. For example,
some secretion inducing agents (e.g. bile acids) may cause
adnominal discomfort when released in certain locations along the
gastrointestinal tract. Traditional capsules may, in some cases,
lead to a burst release of CDC (e.g., resulting in massive phasic
contractions in a subject, resulting in abdominal pain. However, as
described herein some embodiments, the delivery system described
may advantageously control the release of the secretion inducing
agent such that it is released only in certain parts of the
gastrointestinal tract, thereby reducing or eliminating abdominal
pain. In this way, abdominal pain to a subject may be avoided or
mitigated.
Exemplary Embodiments
[0091] In one aspect, an article configured for release of a
therapeutic agent in a colon of a subject is described. In some
embodiments, the article comprises a first portion comprising a
secretion inducing agent and a second portion, adjacent to the
first portion, where the second portion comprises a therapeutic
agent. Certain embodiments of the article may also be configured
with a degradable coating.
[0092] In certain aspects, an article configured to release a
therapeutic agent in a portion of an intestine of a subject is
described. Some embodiments of the article comprise a first
component configured to increase the amount of intestinal fluid
present in the intestine of the subject and a second component
associated with the first component configured to release a
therapeutic agent in the intestine of the subject.
[0093] In another aspect, a method of intestinal drug delivery is
described. The method comprises exposing a portion of an intestine
of a subject to an intestinal secretion inducing agent such that
the intestine is induced to release intestinal fluids. In some
embodiments, the method provides a therapeutic agent to a portion
of a intestine of the subject such that the secretion inducing
agent increases the amount of the therapeutic agent available for
absorption by the intestine of the subject.
[0094] In yet another aspect, a method for administering an
article, comprising a therapeutic agent, to a subject is described.
In some embodiments, the method comprises administering an article
to the subject and releasing a therapeutic agent from the article
to a small intestine of the subject. Certain embodiments of the
method use an article that comprises a first portion comprising a
secretion inducing agent; a second portion, adjacent to the first
portion, comprising the therapeutic agent; and a degradable coating
associated with the article. In some embodiments, the secretion
inducing agent is configured to increase the amount of intestinal
fluid present in a small intestine of the subject.
EXAMPLES
[0095] The following examples are intended to illustrate certain
embodiments of the present invention, but do not exemplify the full
scope of the invention.
Example 1
[0096] This example describes the fabrication and testing of an
exemplary tablet for delivery of a therapeutic agent, in accordance
with certain embodiments.
[0097] The system consists of an article (e.g., a tablet) having a
two-layer core and an Eurdragit S100 coating. The first, extended
release, layer comprises 81% Na-CDC, 17% Hydroxypropylmethyl
cellulose (MW:120.000) and 2% magnesium stearate. The second, boost
release, layer comprises 98% Na-CDC and 2% magnesium stearate.
Two-layer tablets (10 mm diameter) were compressed using a NP-RD10A
tablet press from Natoli (Force: 20,000 N). Each pill contains a
booster layer of 98 mg and an extended release layer of 400 mg
Na-CDC. The tablets were coated with Eurdragit S100 coating
following the manufacturer's recommendations. Briefly, Eudragit
S100 coating solution was prepared by dissolving and homogenizing
Eudragit S100, magnesium stearate and triethyl citrate in a solvent
mixture composed of water, acetone and isopropanol. The tablets
were spray-coated using an Erweka AR403 pan coater.
[0098] Control experiments were performed using capsules prepared
by filling lg of Na-CDC into a gelatin capsules. The capsules were
coated by dip coating using Eudragit S100.
[0099] Dissolution experiments were performed using a Hanson Vision
dissolution testing system. Dissolution was assessed in 800 mL
phosphate buffer (0.2M, pH 6.8 formulation, 37 C, stirred at 50
rpm). After 2 hours pH was changed to 7.4 (2 M NaOH).
[0100] The release kinetics of the delivery system was assessed in
comparison to the clinical reference product (1g Na-CDC capsules
coated with Eudragit S 100, FIGS. 7A-7B). To simulate passage
through the gastrointestinal tract release was assessed in
phosphate buffer (pH 6.8) for two hours and pH 7.4. Na-CDC release
from the clinical reference product plateaus after 2 hours. Drug
release from delivery system is detectable after 2 hours and a
total of 70 mg Na-CDC is released within the first 30 minutes.
Thereafter controlled Na-CDC release follows zero order kinetics
for 20 hours. Swellable HPMC within the delivery system facilitates
a pH independent release mechanism (FIG. 8) shows the inflow of
medium into the system induces swelling which promotes diffusion of
Ca-CDC through the coating layer.
Example 2
[0101] This example describes the fabrication and testing of an
exemplary tablet for delivery of a therapeutic agent, in accordance
with certain embodiments.
[0102] FIG. 7 shows the in-vitro dissolution profile of a capsule
filled with lg Na-CDC (Eudragit S100 coated)FIG 10 A) shows the in
vitro dissolution profile of delivery systems comprising 0.5 g
Na-CDC (Eudragit S100 coated). The systems where immersed in
Simulated Gastric Fluid (SGF, 1 h) and in 0.2M phosphate buffer
("intestinal fluid", pH 6.8, 1 h) before pH was adjusted to 7.4 (2
M NaOH) after another hour. The single layered delivery system
demonstrates the release profile of a formulation containing only
the "therapeutic drug layer" (0.5 g NaCDC/HPMC) without the
"booster layer". In-vivo pharmacokinetic profile in swine of B) The
capsule (A),C) 2 delivery system (bilayer) and D) 2 single layered
delivery systems demonstrating extended release in vivo. Increased
chenodeoxycholic acid (CDCA) serum levels in the bilayer group as
compared to the single layered group demonstrates increased
dissolution in accordance with certain embodiments. In vitro
dissolution experiments (FIG. 10A) were performed using a Hanson
(Chatsworth, Calif.) Vision dissolution testing system (37 C,
stirred at 100 rpm). The delivery systems were exposed to 800 mL
Simulated Gastric Fluid (SGF, without enzymes, USP) for one hour,
before the systems were transferred to Simulated Intestinal Fluid
for 1 hour (SIF, without enzymes, pH 6.8). After 1 hour the pH was
adjusted to 7.4 (2 M NaOH).
Example 3
[0103] The following example demonstrates the administration of an
article described herein.
[0104] Without wishing to be bound by theory, burst release of
Chenodeoxycholate (CDC) from a traditional capsule can trigger
massive contractions which the patient feels as abdominal pain.
This was previously shown for bile acids in man at a concentration
over 3 mM.
[0105] Intrarectal pressure was measured following rectal placement
of the traditional CDC "capsule" and the bilayered "delivery
system" (e.g., an article as described herein) along with 50 mL
saline. The capsule is 1 g NaCDC (the "capsule). The bilayered
"delivery system" described here used 0.5 g NaCDC. As shown in FIG.
4, massive contractions in pigs were observed in pigs receiving the
capsule but not in those receiving the delivery system or not
receiving delivery systems (control).
Example 4
[0106] The following example demonstrates exemplary configurations
of various articles, described herein.
[0107] FIGS. 5-6 show an exemplary capsule manufactured as
described herein.
[0108] The first portion may comprise about 98% NaCDC as a
secretion inducing agent and about 2% and 0.5% magnesium stearate
and Aerosil.RTM. 200 Pharma, respectively, as additional components
or excipients The second portion may comprise about 88% NaCDC, 10%
HPMC, 2% magnesium stearate, and 0.5% Aerosil.RTM. 200 Pharmaln
some embodiments, the total amount of NaCDC is 500 mg. In some
embodiments, the weight of an article (e.g. a pill) is about 557
mg.
[0109] FIGS. 8A-8B are photographs of exemplary articles, as
described herein. FIG. 9 is a schematic illustration of an
exemplary article comprising a Na-CDC layer and a 5-aminosalycic
acid layer.
[0110] FIG. 10A is a plot of dissolution of NaCDC (g) versus time
for traditional capsules (FIG. 7A) versus the inventive articles
described herein.
[0111] FIGS. 10B-D are plots of pharmacokinetic profiles of NaCDC
versus time for traditional capsules (FIG. 7A) and traditional
controlled release system (single layered) versus the inventive
article described herein.
Example 5
[0112] The following example describes exemplary in vivo porcine
studies using various articles, described herein.
[0113] All procedures were conducted in accordance with protocols
approved by the Massachusetts Institute of Technology Committee on
Animal. Twelve separate female Yorkshire pigs weighing
approximately 30-50 kg were randomly assigned for in vivo
evaluation. Following overnight fasting, the animals were sedated
with Telazol (tiletamine/zolazepam) 5 mg/kg, xylazine 2 mg/kg, and
atropine 0.04 mg/kg. Endotracheal intubation was performed, and
anesthesia was maintained with isoflurane thereafter (1-3% in
oxygen). For pharmacokinetic studies, the delivery systems were
placed into the small intestine by using an esophageal overtube (US
Endoscopy, Mentor, Ohio) with endoscopic guidance. Blood was
sampled through a central venous catheter or through mammal bleeds
in case catheter placement was not possible.
[0114] CDCA in serum from these in vivo experiments were analyzed
using Ultra-Performance Liquid Chromatography-Tandem Mass
Spectrometry (UPLC-MS/MS). Analysis was performed on a Waters
ACQUITY UPLC.RTM.-I-Class System aligned with a Waters Xevo.RTM.
TQ-S mass spectrometer (Waters Corporation, Milford Mass.). Liquid
chromatographic separation was performed on an Acquity UPLC.RTM.
HSS T3 (50 mm.times.2.1 mm, 1.8 .mu.m particle size) column at
50.degree. C. The mobile phase consisted of aqueous 0.1% formic
acid, 10 mM ammonium formate solution (Mobile Phase A) and
acetonitrile: 10 mM ammonium formate, 0.1% formic acid solution
(95:5 v/v) (Mobile Phase B). The mobile phase had a continuous flow
rate of 0.6 mL/min using a time and solvent gradient
composition.
[0115] For the analysis of CDCA, the initial composition, 95%
Mobile Phase A, was held for 1.00 minutes, following which the
composition was changed linearly to 2% Mobile Phase A until 1.80
minutes. The composition of 2% Mobile Phase A and 98% Mobile Phase
B was held constant until 3.00 minutes. The composition linearly
changed to 80% Mobile Phase A at 3.50 minutes and was linearly
returned to 95% Mobile Phase A until completion of the run, ending
at 4.50 minutes, where it remained for column equilibration. The
total run time was 4.50 minutes. The mass to charge transitions
(m/z) used to quantitate CDCA was 391.452>391.591. For internal
standard, d-4 CDCA, 395.38 >396.07 m/z transition was used for
quantitation.
[0116] Sample introduction and ionization was by electrospray
ionization (ESI) in the positive ionization mode. Waters MassLynx
4.1 software was used for data acquisition and analysis. Stock
solutions were prepared in methanol at a concentration of 500
.mu.g/mL. A twelve-point calibration curve was prepared in
analyte-free, blank serum ranging from 1.25-5000 ng/mL. 100 .mu.l
of each serum sample was spiked with 200 .mu.l of 250 ng/mL
internal standard in acetonitrile to elicit protein precipitation.
Samples were vortexed, sonicated for 10 minutes, and centrifuged
for 10 minutes at 13,000 rpm. 200 .mu.l of supernatant was pipetted
into a 96-well plate containing 200 .mu.l of water. Finally, 10.00
.mu.l was injected onto the UPLC-ESI-MS system for analysis. One
serum sample was lost (72 h, single layered) and we included a
fourth animal for this group.
[0117] CDCA concentrations were then analyzed utilizing an Agilent
(Santa Clara, Calif.) 1260 Infinity II HPLC system equipped with an
Agilent 6120B mass spectrometer. Data processing and analysis was
performed using OpenLab CDS ChemStation (Agilent). Isocratic
separation was achieved using an Agilent 4.6.times.50 mm EC C-18
Poroshell column with 2.7 .mu.m particles, maintained at 55.degree.
C. The mobile phase consisted of 20% 10 mM ammonium acetate in
water (unbuffered) and 80% methanol using a flow rate of 0.850
mL/min over a period of 6 minutes. Gradient separation was achieved
over a 5 min run time (3 min post run). The injection volume was 5
.mu.L, and the selected ultraviolet (UV) detection wavelength was
210 nm at an acquisition rate of 5 Hz. The ESI drying gas flow rate
and temperature was 10 L/min and 350.degree. C., accordingly. The
SIM of CDC and CA internal standard were analyzed using negative
mode electron spray ionization at a gain of 2.00, fragmentor of 70,
monitoring mass-to-charge ratios of 391.40 m/z and 408.60 m/z,
respectively.
[0118] Disintegration of bilayer systems in vivo was profiled in a
terminal procedure in swine. After sedation and intubation with
isoflurane, a laparotomy was performed using a ventral middle line
incision from the xiphoid to the pubis. The delivery systems were
then placed through an incision into the duodenum and retrieved 4
hours later. A set of unrelated different experiments were
performed concurrently during the terminal procedure but did not
interfere with the GI tract either physically nor
pharmacologically.
[0119] To understand in vivo disintegration characteristics of the
delivery system, the release systems were retrieved following
intestinal passage in swine during a terminal procedure. 91.6% (11
systems) of the release systems placed into the SI (12) remained
intact until retrieval 4 hours after implantation (FIGS. 12A-12B,
FIG. 13; see FIG. 13B for partly disintegrated system).
Example 6
[0120] The following example describes exemplary rectal manometry
of various articles described herein to assess rectal motility.
[0121] The effect of bile acid formulations on rectal motility was
analyzed. Therefore, the rectum was cleaned with .about.120 mL
saline infused through a Foley catheter. One uncoated CDC capsule
or one uncoated bilayer delivery system was applied rectally along
with 50 mL saline before measurement was started. No CDC was
applied in the control group. The measurement was done by rectal
placement of an air inflated balloon connected (PVC tube) to a
micro pressure sensor (MPRLS ,Honeywell Charlotte, N.C.). The
sampling frequency of the was 30 Hz. An ultralow band pass Finite
Impulse Response (FIR) filter was used (MATLAB, MathWorks, Natick,
Mass.) with cutoff frequency of 0.1 Hz, to filter auxiliary signals
(respiration) and identify rectal motility.
[0122] A clinical challenge of colonic CDC delivery is noticeable
abdominal cramping and pain in patients. It was hypothesized that
this symptom was due to massive contractions triggered by local
super-physiological CDC levels within the proximal colon. Thus
rectal manometry was performed following placement of uncoated CDC
capsules and bilayer systems in comparison to the control receiving
no treatment. Approximately 15 minutes after rectal application,
repeated massive contractions in all pigs receiving CDC capsules by
measuring the pressure variation in colon (FIG. 12C). FIG. 12D
shows the unified and filtered colon pressure variation by means of
a low pass filter. In the group receiving the bilayer system, only
one major contraction was observed. In the control group no massive
contractions were observed.
Example 7
[0123] The following example describes exemplary in vitro and in
silico studies of various articles described herein.
[0124] Dissolution experiments were performed using a Hanson
(Chatsworth, Calif.) Vision Elite 8 dissolution testing system
(37.degree. C., stirred at 100 rpm). The delivery systems were
exposed to 800 mL of Simulated Gastric Fluid (SGF, without enzymes,
USP) for one hour, before transferring to Simulated Intestinal
Fluid for 1 hour (SIF, without enzymes, pH 6.8). After one hour,
the pH was adjusted to 7.4 (2 M NaOH). In another set of
experiments, the CDC capsules and bilayer pills were exposed to SIF
(pH 6.8, 1 hour) for one hour before they were transferred to SIF
(pH 7.4). These experiments were performed at 50 rpm under
otherwise identical conditions.
[0125] For pharmacokinetic in silico simulations, Symbiology from
MathWorks (Natick, Mass.) was used to generate a five-compartment
gastrointestinal model (see Supplementary FIG. 2 for setup). The
compartments modeled were the caecum, ascending colon, transverse
colon, descending colon, and sigmoid. First-order kinetics were
assumed for all reactions. For parametric data, a one-way ANOVA
following post-hoc Duncan test was used. A p.ltoreq.0.05 was
considered statistically significant.
TABLE-US-00001 Volume Half transit time Rate Part [mL] [hour]
[hour.sup.-1] (=K) Caecum (CAE) 50 1 0.693 Ascending colon (AC) 203
2.5 0.277 Transverse colon (TC) 198 2.9 0.239 Descending colon (DC)
160 5.5 0.126 Sigmoid (SC) 250 12.1 0.057 Assuming first order
kinetics and an average bile acid concentration of 2 mM:
K.sub.abs(0-5) = 0.323 h.sup.-1 V.sub.d = 25.81 L/Kg (1600 L/62 Kg)
Estimated pig weight: 40 Kg Cl = 25 L/h .fwdarw. k.sub.eli =
0.024218939 h.sup.-1
[0126] Following pH triggered disintegration of Eudragit S100, CDC
was immediately and completely released with a half-life of 0.5
hours from the capsule formulation (100 rounds per minute (rpm),
FIG. 14A; lag time: 1.5 hours). Under identical conditions, the
bilayer system released CDC following first order kinetics with a
half-life of approximately 2.5 hours (FIG. 14; lag time: 2 hours).
The single layer system, serving as control for a conventional
colonic drug delivery system with sustained release kinetics,
released CDC with a half-life of approximately 6 hours (FIG. 14G;
lag time: 2 hours).
[0127] Importantly, when performing the release experiment at 50
rpm, it was observed that a biphasic release pattern initially
releasing .about.150 mg CDC within 3 hours after pH triggered
disintegration (FIG. 15A). Following first order kinetics, the
bilayer tablet released CDC over a course 16 hours thereafter
(.about.80% CDC released). Under identical conditions (e.g., 50
rpm) the capsule formulation released its full payload within 0.5
hours (FIG. 15B).
[0128] To better understand local colonic CDC levels, a
six-compartment pharmacokinetic in silico model based on
physiological characteristics and the in vitro pharmacokinetic
profile of the delivery systems. Local colonic peak concentrations
of 16.2 (6.2 hours), 5.0 (7 hours), and 2.2 mM (7 hours) were
observed for the capsule, for the bilayer and the single layer
formulation respectively (FIGS. 14B, E and H). Modeled systemic CDC
levels reached c.sub.max after 19.3 hours (1696 ng/mL), 21.6 hours
(1694.7 ng/mL), and 27.45 hours (1477 ng/mL) respectively (FIGS.
14C, F and I). In vivo serum CDCA levels following intestinal
placement of the delivery systems matched modelled levels, and
c.sub.max was 1182.+-.296.43 (24 hours), 3895.93.+-.2725.87 (24
hours) and 1409.40.+-.1825.31 (72 hours) for capsule, bilayer and
single layer respectively (FIGS. 14C, F and I). Control experiments
were performed in pigs not receiving CDC. Maximal CDCA levels were
87.36.+-.107.63 in this group (FIGS. 14C, F and L).
[0129] Pharmacokinetic evaluation of the bilayer delivery system
versus traditional formulations are made in FIG. 14. In vitro
release pattern of 1 g CDC capsules (FIG. 14A), bilayered delivery
systems in FIG. 14D, single layered delivery systems in FIG. 14G
(serving as control for a conventional extended release delivery
system, exposed to Simulated Gastric Fluid (SGF, 1 h), Simulated
Intestinal Fluid (0.2M, SIF, pH 6.8, 1 h) and SIF (0.2M, pH 7.4),
respectively (100 rpm)). An in silico pharmacokinetic model was
used to understand CDC levels over time in the colon. In FIG. 14B,
1 g CDC capsule are shown, in FIG. 14E, the bilayered delivery
system (2.times.) is used, and in FIG. 14H, the single layered
delivery system (2.times.) is shown. For comparison FIG. 14K shows
colonic CDC levels that have previously been linked to secretory,
prokinetic, distinct prokinetic effects and are shown in comparison
to phycological bile acid levels. The pharmacokinetic model was
also used to predict systemic bile acid levels in swine (dashed
line) which are shown in comparison to systemic levels (solid
lines, LC-MS) for C) 1 g CDC capsules a F) bilayered delivery
systems (2.times.) and I) a single layered delivery system
(2.times., n=4). Results are depicted as mean of n=3.+-.SD unless
otherwise noted (*p<0.05).
[0130] While several embodiments of the present invention have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present invention. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present invention
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. It is, therefore, to be understood that the foregoing
embodiments are presented by way of example only and that, within
the scope of the appended claims and equivalents thereto, the
invention may be practiced otherwise than as specifically described
and claimed. The present invention is directed to each individual
feature, system, article, material, and/or method described herein.
In addition, any combination of two or more such features, systems,
articles, materials, and/or methods, if such features, systems,
articles, materials, and/or methods are not mutually inconsistent,
is included within the scope of the present invention.
[0131] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0132] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified unless clearly
indicated to the contrary. Thus, as a non-limiting example, a
reference to "A and/or B," when used in conjunction with open-ended
language such as "comprising" can refer, in one embodiment, to A
without B (optionally including elements other than B); in another
embodiment, to B without A (optionally including elements other
than A); in yet another embodiment, to both A and B (optionally
including other elements); etc.
[0133] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0134] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0135] Some embodiments may be embodied as a method, of which
various examples have been described. The acts performed as part of
the methods may be ordered in any suitable way. Accordingly,
embodiments may be constructed in which acts are performed in an
order different than illustrated, which may include different
(e.g., more or less) acts than those that are described, and/or
that may involve performing some acts simultaneously, even though
the acts are shown as being performed sequentially in the
embodiments specifically described above.
[0136] Use of ordinal terms such as "first," "second," "third,"
etc., in the claims to modify a claim element does not by itself
connote any priority, precedence, or order of one claim element
over another or the temporal order in which acts of a method are
performed, but are used merely as labels to distinguish one claim
element having a certain name from another element having a same
name (but for use of the ordinal term) to distinguish the claim
elements.
[0137] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," and the like are to
be understood to be open-ended, i.e., to mean including but not
limited to. Only the transitional phrases "consisting of" and
"consisting essentially of" shall be closed or semi-closed
transitional phrases, respectively, as set forth in the United
States Patent Office Manual of Patent Examining Procedures, Section
2111.03.
* * * * *