U.S. patent application number 17/720814 was filed with the patent office on 2022-07-28 for stable formulations of linaclotide.
The applicant listed for this patent is Forest Laboratories Holdings Limited, Ironwood Pharmaceuticals, Inc.. Invention is credited to Brian Cali, Mahendra Dedhiya, Angelika Fretzen, Yun Mo.
Application Number | 20220233635 17/720814 |
Document ID | / |
Family ID | 1000006261724 |
Filed Date | 2022-07-28 |
United States Patent
Application |
20220233635 |
Kind Code |
A1 |
Mo; Yun ; et al. |
July 28, 2022 |
Stable Formulations of Linaclotide
Abstract
The present invention relates to stable pharmaceutical
compositions comprising linaclotide or pharmaceutically acceptable
salts thereof, as well as to various methods and processes for the
preparation and use of the compositions.
Inventors: |
Mo; Yun; (Commack, NY)
; Fretzen; Angelika; (Somerville, MA) ; Cali;
Brian; (Arlington, MA) ; Dedhiya; Mahendra;
(Pomona, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ironwood Pharmaceuticals, Inc.
Forest Laboratories Holdings Limited |
Boston
Hamilton |
MA |
US
BM |
|
|
Family ID: |
1000006261724 |
Appl. No.: |
17/720814 |
Filed: |
April 14, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17465006 |
Sep 2, 2021 |
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17720814 |
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17147915 |
Jan 13, 2021 |
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17465006 |
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16864533 |
May 1, 2020 |
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17147915 |
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16575477 |
Sep 19, 2019 |
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16864533 |
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16264792 |
Feb 1, 2019 |
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16575477 |
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16006070 |
Jun 12, 2018 |
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16264792 |
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15727700 |
Oct 9, 2017 |
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16006070 |
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15439049 |
Feb 22, 2017 |
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15727700 |
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15203951 |
Jul 7, 2016 |
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15439049 |
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14948795 |
Nov 23, 2015 |
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15203951 |
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14689561 |
Apr 17, 2015 |
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14948795 |
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14484568 |
Sep 12, 2014 |
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14689561 |
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13816154 |
Sep 10, 2013 |
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PCT/US2011/047434 |
Aug 11, 2011 |
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14484568 |
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61372804 |
Aug 11, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1611 20130101;
A61K 9/1676 20130101; A61K 38/10 20130101; A61K 47/18 20130101;
A61K 9/1641 20130101; A61K 38/12 20130101 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61K 9/16 20060101 A61K009/16; A61K 38/10 20060101
A61K038/10; A61K 47/18 20060101 A61K047/18 |
Claims
1. A pharmaceutical composition comprising linaclotide, a cation or
pharmaceutically acceptable salt thereof and an amine selected from
meglumine or a mixture of meglumine and histidine.
2. The composition of claim 1, wherein the amine is meglumine.
3. A pharmaceutical composition comprising linaclotide, a cation or
pharmaceutically acceptable salt thereof and histidine, wherein the
composition has a molar ratio of cation:histidine of less than
2:1.
4. The composition of claim 1 or claim 3, wherein the composition
further comprises a polymer.
5. The composition of claim 4, wherein the polymer is selected from
polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or a mixture
thereof
6. A method of treating a gastrointestinal disorder comprising
administering to a patient in need thereof, a therapeutically
effective amount of the composition of claim 1 or claim 3.
7. The method of claim 6, wherein the gastrointestinal disorder is
selected from the group consisting of irritable bowel syndrome,
chronic constipation, opioid induced constipation and
dyspepsia.
8. The method of claim 7, wherein the gastrointestinal disorder is
chronic constipation.
9. The method of claim 7, wherein the gastrointestinal disorder is
constipation-predominant irritable bowel syndrome.
10. A method of making the composition of claim 1, comprising
combining linaclotide with a cation or pharmaceutically acceptable
salt thereof and an amine selected from meglumine or a mixture of
meglumine and histidine.
11. A composition prepared by the method of claim 10.
12. A method of making the composition of claim 3, comprising
combining linaclotide with a cation or pharmaceutically acceptable
salt thereof and histidine, wherein the composition has a molar
ratio of cation:histidine of less than 2:1.
13. A composition prepared by the method of claim 12.
14. A pharmaceutical composition comprising linaclotide, a cation
or pharmaceutically acceptable salt thereof and a dipeptide
selected from glycine-leucine, leucine-glycine, or a mixture
thereof.
15. The composition of claim 14, wherein the composition further
comprises a polymer.
16. The composition of claim 15, wherein the polymer is selected
from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or a
mixture thereof
17. A method of treating a gastrointestinal disorder comprising
administering to a patient in need thereof, a therapeutically
effective amount of the composition of claim 14.
18. The method of claim 17, wherein the gastrointestinal disorder
is selected from the group consisting of irritable bowel syndrome,
chronic constipation, opioid induced constipation and
dyspepsia.
19. The method of claim 18, wherein the gastrointestinal disorder
is chronic constipation.
20. The method of claim 18, wherein the gastrointestinal disorder
is constipation-predominant irritable bowel syndrome.
21. A method of making the composition of claim 14, comprising
combining linaclotide with a cation or pharmaceutically acceptable
salt thereof and a dipeptide selected from glycine-leucine,
leucine-glycine, or a mixture thereof.
22. A composition prepared by the method of claim 21.
23. The composition of claim 1, wherein the composition comprises
Ca.sup.2+ and an amino acid selected from meglumine or mixture of
meglumine and histidine in a molar ratio of Ca.sup.2+:amino acid
between about 1.3:1 and 0.7:1.
24. The composition of claim 1, wherein the composition comprises
Ca.sup.2+ and an amino acid selected from meglumine or mixture of
meglumine and histidine in a molar ratio of Ca.sup.2+:amino acid
between about 1.1:1 and 0.9:1.
25. The composition of claim 3, wherein the composition comprises
Ca.sup.2+ and histidine in a molar ratio of Ca.sup.2+:histidine
between about 1.3:1 and 0.7:1.
26. The composition of claim 3, wherein the composition comprises
Ca.sup.2+ and histidine in a molar ratio of Ca.sup.2+:histidine
between about 1.1:1 and 0.9:1.
Description
CLAIM OF PRIORITY
[0001] This application is a continuation of U.S. patent
application Ser. No. 17/465,006 filed Sep. 2, 2021, which is a
continuation of U.S. patent application Ser. No. 17/147,915 filed
Jan. 13, 2021, which is a continuation of U.S. patent application
Ser. No. 16/575,477 filed Sep. 19, 2019, which is the continuation
of U.S. patent application Ser. No. 16/264,792 filed Feb. 1, 2019,
which is the continuation of U.S. patent application Ser. No.
16/006,070 filed Jun. 12, 2018, which is the continuation of U.S.
patent application Ser. No. 15/727,700 filed Oct. 9, 2017, which is
the continuation of U.S. patent application Ser. No. 15/439,049
filed Feb. 22, 2017, which is the continuation of U.S. patent
application Ser. No. 15/203,951 filed Jul. 7, 2016, which is the
continuation of U.S. patent application Ser. No. 14/948,795 filed
Nov. 23, 2015, which is the continuation of U.S. patent application
Ser. No. 14/689,561 filed Apr. 17, 2015, which is the continuation
U.S. patent application Ser. No. 14/484,568 filed Sep. 12, 2014,
which is the continuation of U.S. patent application Ser. No.
13/816,154 filed Sep. 10, 2013, which is the United States national
phase application of PCT/US2011/047434, filed on Aug. 11, 2011.
This application also claims priority to U.S. Provisional Patent
Application Ser. No. 61/372,804 filed Aug. 11, 2010. The entire
contents of the aforementioned applications are incorporated herein
by reference.
SEQUENCE LISTING
[0002] This application incorporates by reference in its entirety
the Sequence Listing entitled "IW099PCT1US1CON2_ST25.txt" which is
620 bytes in size and last modified on Apr. 17, 2015 and filed
electronically herewith.
FIELD OF THE INVENTION
[0003] The present invention relates to stable pharmaceutical
compositions of linaclotide and methods for treating
gastrointestinal disorders (e.g., irritable bowel syndrome or
chronic constipation) by administering the pharmaceutical
compositions.
BACKGROUND OF THE INVENTION
[0004] Linaclotide is a peptide that is useful as an agonist of the
guanylate cyclase C (GC-C) receptor in the treatment of
gastrointestinal disorders. Linaclotide is described, for example,
in U.S. Pat. Nos. 7,304,036 and 7,371,727, the contents of which
are incorporated herein by reference in their entirety.
[0005] There is an existing and continual need for linaclotide
formulations, for example, low-dose and pediatric formulations,
having improved stability and performance. This need arises in part
because of the intrinsic and chemical instability of linaclotide
(for example, induced by moisture-driven degradation reactions such
as hydrolysis, deamidation, isomerization, and multimerization).
These difficulties may be exacerbated when producing pediatric
formulations and other low-dose formulations of linaclotide, e.g.,
because the linaclotide is more dispersed and has greater surface
area exposure to aqueous environments such as during
preparation.
[0006] The present invention provides such improved stability
formulations of linaclotide. These formulations are described
herein.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 illustrates stability performance data for the
linaclotide compositions prepared in Examples 2-5 as described in
Example 6.
SUMMARY OF THE INVENTION
[0008] In some embodiments of the present invention, a stable
pharmaceutical composition is provided which comprises linaclotide,
a cation or salt thereof, and a sterically hindered amine selected
from meglumine, histidine or a mixture thereof, and, optionally, a
polymer.
[0009] In some embodiments, the pharmaceutical composition
comprises linaclotide, a cation or pharmaceutically acceptable salt
thereof and an amine selected from meglumine or a mixture of
meglumine and histidine.
[0010] In some embodiments, the pharmaceutical composition
comprises linaclotide, a cation or pharmaceutically acceptable salt
thereof and histidine, wherein the composition has a molar ratio of
cation:histidine of less than 2:1.
[0011] In some embodiments, a stable pharmaceutical composition is
provided which comprises linaclotide,a cation or salt thereof,
meglumine, and, optionally, a polymer.
[0012] In some embodiments, a stable pharmaceutical composition is
provided which comprises linaclotide, a cation or salt thereof,
histidine, and, optionally, a polymer.
[0013] In some embodiments, the pharmaceutical composition further
comprises a polymer.
[0014] In some embodiments, a pharmaceutical composition (e.g.,
capsule, tablet, granule or bead) is provided which comprises
linaclotide, a cation or pharmaceutically acceptable salt thereof,
a sterically hindered amine selected from histidine, meglumine or a
mixture thereof, and a polymer selected from polyvinyl pyrrolidone
(PVP), polyvinyl alcohol (PVA) or a mixture thereof.
[0015] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and melamine. In some embodiments, the
pharmaceutical composition further comprises a polymer.
[0016] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and gelatin. In some embodiments, the
pharmaceutical composition further comprises a polymer.
[0017] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and glycine. In some embodiments, the
pharmaceutical composition further comprises a polymer.
[0018] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and the dipeptide glycine-leucine. In some
embodiments, the pharmaceutical composition further comprises a
polymer.
[0019] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and the dipeptide leucine-glycine. In some
embodiments, the pharmaceutical composition further comprises a
polymer.
[0020] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and albumin. In some embodiments, the
pharmaceutical composition further comprises a polymer.
[0021] In some embodiments, a pharmaceutical composition is
provided which comprises linaclotide, a cation or pharmaceutically
acceptable salt thereof, and asparagine. In some embodiments, the
pharmaceutical composition further comprises a polymer.
[0022] In some embodiments, a stable low-dose pharmaceutical
composition of linaclotide is provided. In some embodiments, a
stable pediatric pharmaceutical composition of linaclotide is
provided.
[0023] In some embodiments, a method of treating a gastrointestinal
disorder comprising administering to a patient in need thereof, a
therapeutically effective amount of the pharmaceutical compositions
described above.
DETAILED DESCRIPTION OF THE INVENTION
[0024] Stable formulations of linaclotide (SEQ ID NO:1) are
provided herein. In addition, methods of using the formulations to
treat gastrointestinal disorders, including irritable bowel
syndrome ("IBS") (for example, constipation-predominant IBS) and/or
constipation (for example, chronic constipation), and processes for
making the compositions are provided.
[0025] It has been found that the stability of linaclotide within
solid oral dosage forms (e.g., capsules and tablets) can be
improved by combining linaclotide with specific concentrations or
molar ratios of a cation or pharmaceutically acceptable salt
thereof, and an amine selected from histidine, meglumine or
combination thereof. In some embodiments, stability may be improved
by combining linaclotide with specific concentrations or molar
ratios of a polymer, cation or pharmaceutically acceptable salt
thereof, and an amine selected from histidine, meglumine or
combination thereof. It has been found, in some embodiments, that
combining these components with linaclotide causes a synergistic
increase or improvement in the stability of linaclotide within the
composition, for example as compared to similar compositions not
containing the cation and/or sterically hindered amine and/or the
same concentrations of these components.
[0026] The pharmaceutical composition may include any effective
amount of linaclotide. In some embodiments, for example, the
composition comprises from 0.001 .mu.g to 400 .mu.g of linaclotide.
In some embodiments, for example, the composition comprises from
0.001 .mu.g to 350 .mu.g of linaclotide. In some embodiments, for
example, the composition comprises from 0.001 .mu.g to 300 .mu.g of
linaclotide. In some embodiments, for example, the composition
comprises from 0.001 .mu.g to 250 .mu.g of linaclotide. In some
embodiments, for example, the composition comprises from 0.001
.mu.g to 200 .mu.g of linaclotide. In some embodiments, for
example, the composition comprises from 0.001 .mu.g to 150 .mu.g of
linaclotide. In some embodiments, for example, the composition
comprises from 0.001 .mu.g to 125 .mu.g of linaclotide. In some
embodiments, for example, the composition comprises from 0.001
.mu.g to 100 .mu.g of linaclotide. In some embodiments, for
example, the composition comprises from 0.001 .mu.g to 80 .mu.g of
linaclotide. In some embodiments, for example, the composition
comprises from 0.001 .mu.g to 60 .mu.g of linaclotide. In some
embodiments, for example, the composition comprises from 0.001
.mu.g to 50 .mu.g of linaclotide. In some embodiments, for example,
the composition comprises from 0.001 .mu.g to 40 .mu.g of
linaclotide. In some embodiments, for example, the composition
comprises from 0.001 .mu.g to 30 .mu.g of linaclotide.
[0027] In some embodiments, the composition comprises 0.001 .mu.g
to 300 .mu.g of linaclotide (e.g., 0.01 .mu.g to 300 .mu.g, 0.1
.mu.g to 300 .mu.g, 1 .mu.g to 300 .mu.g, 5 .mu.g to 300 .mu.g, 10
.mu.g to 300 .mu.g, 25 .mu.g to 300 .mu.g, or 50 .mu.g to 300 .mu.g
of linaclotide). In some embodiments, the composition comprises
0.001 .mu.g to 200 .mu.g of linaclotide (e.g., 0.01 .mu.g to 200
.mu.g, 0.1 .mu.g to 200 .mu.g, 1 .mu.g to 200 .mu.g, 5 .mu.g to 200
.mu.g, 10 .mu.g to 200 .mu.g, 25 .mu.g to 200 .mu.g, or 50 .mu.g to
200 .mu.g of linaclotide). In some embodiments, the composition
comprises 0.001 .mu.g to 125 .mu.g of linaclotide (e.g., 0.01 .mu.g
to 125 .mu.g, 0.1 .mu.g to 125 .mu.g, 1 .mu.g to 125 .mu.g, 5 .mu.g
to 125 .mu.g, 10 .mu.g to 125 .mu.g, 25 .mu.g to 125 .mu.g, or 50
.mu.g to 125 .mu.g of linaclotide). In some embodiments, the
composition comprises 0.01 .mu.g to 100 .mu.g of linaclotide (e.g.,
0.1 .mu.g to 100 .mu.g, 1 .mu.g to 100 .mu.g, 5 .mu.g to 100 .mu.g,
10 .mu.g to 100 .mu.g, 25 .mu.g to 100 .mu.g, or 50 .mu.g to 100
.mu.g of linaclotide). In some embodiments, the composition
comprises 0.01 .mu.g to 75 .mu.g of linaclotide (e.g., 0.1 .mu.g to
75 .mu.g, 1 .mu.g to 75 .mu.g, 5 .mu.g to 75 .mu.g, 10 .mu.g to 75
.mu.g, 25 .mu.g to 75 .mu.g, or 50 .mu.g to 75 .mu.g of
linaclotide). In some embodiments, the composition comprises 0.01
.mu.g to 50 .mu.g of linaclotide (e.g., 0.1 .mu.g to 50 .mu.g, 1
.mu.g to 50 .mu.g, 5 .mu.g to 50 .mu.g, 10 .mu.g to 50 .mu.g, or 20
.mu.g to 50 .mu.g of linaclotide).
[0028] In some embodiments, the composition comprises 0.001 .mu.g,
0.005 .mu.g, 0.01 .mu.g, 0.05 .mu.g, 0.1 .mu.g, 0.15 .mu.g, 0.25
.mu.g, 0.5 .mu.g, 0.75 .mu.g, 1 .mu.g, 2.5 .mu.g, 5 .mu.g, 7.5
.mu.g, 10 .mu.g, 20 .mu.g, 30 .mu.g, 40 .mu.g, 50 .mu.g, 60 .mu.g,
80 .mu.g, 100 .mu.g, 125 .mu.g, 133 .mu.g, 150 .mu.g, 200 .mu.g,
250 .mu.g, 266 .mu.g, 300 .mu.g, 350 .mu.g, 400 .mu.g, 450 .mu.g,
500 .mu.g, 550 .mu.g, 600 .mu.g, 650 .mu.g, 700 .mu.g, 750 .mu.g,
800 .mu.g, 850 .mu.g, 900 .mu.g, 950 .mu.g or 1 mg of linaclotide.
In some embodiments, the composition comprises 75 .mu.g of
linaclotide. In some embodiments, the composition comprises 133
.mu.g of linaclotide. In some embodiments, the composition
comprises 150 .mu.g of linaclotide. In some embodiments, the
composition comprises 266 .mu.g of linaclotide. In some
embodiments, the composition comprises 300 .mu.g of linaclotide. In
some embodiments, the composition comprises 600 .mu.g of
linaclotide.
[0029] In some embodiments, the pharmaceutical composition (e.g.,
bead or granule) comprises 0.00001 to 5% by weight of linaclotide,
for example, 0.00001 to 3% by weight, 0.00001 to 1% by weight,
0.0001 to 0.5% by weight, 0.0001 to 0.3% by weight, 0.0001 to 0.1%
by weight, 0.0001 to 0.07 wt. %, 0.0005 to 0.05 wt. %, 0.005 to
0.04 wt. %, 0.008 to 0.03 wt. %, 0.008 to 0.02 wt. %, 0.008 to
0.015 wt. %, or about 0.012% by weight of linaclotide.
In some embodiments, the pharmaceutical composition also comprises
meglumine, histidine or a combination or mixture thereof. In some
embodiments, the pharmaceutical composition comprises linaclotide,
a cation or pharmaceutically acceptable salt thereof and an amine
selected from meglumine or a mixture of meglumine and histidine. In
other embodiments, the pharmaceutical composition comprises
linaclotide, a cation or pharmaceutically acceptable salt thereof
and histidine, wherein the composition has a molar ratio of
cation:histidine of less than 2:1. For example, in some
embodiments, the pharmaceutical composition comprises meglumine. In
some embodiments, the pharmaceutical composition comprises
histidine. In some embodiments, the pharmaceutical composition
comprises meglumine and histidine.
[0030] The pharmaceutical composition can comprise any stabilizing
amount of meglumine, histidine or mixture thereof. In some
embodiments, for example, the composition comprises a molar ratio
of meglumine, histidine (or mixture thereof) to linaclotide between
100:1 and 1:100. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 100:1 and 1:1. In some embodiments, the
composition comprises a molar ratio of meglumine, histidine (or
mixture thereof) to linaclotide between 90:1 and 2:1. In some
embodiments, the composition comprises a molar ratio of meglumine,
histidine (or mixture thereof) to linaclotide between 80:1 and 5:1.
In some embodiments, the composition comprises a molar ratio of
meglumine, histidine (or mixture thereof) to linaclotide between
70:1 and 10:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 60:1 and 20:1. In some embodiments, the
composition comprises a molar ratio of meglumine, histidine (or
mixture thereof) to linaclotide between 50:1 and 30:1. In some
embodiments, the composition comprises a molar ratio of meglumine,
histidine (or mixture thereof) to linaclotide between 40:1 and
20:1. In some embodiments, the composition comprises a molar ratio
of meglumine, histidine (or mixture thereof) to linaclotide between
100:1 and 20:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 100:1 and 25:1.
[0031] In some embodiments, the composition comprises a molar ratio
of meglumine, histidine (or mixture thereof) to linaclotide between
100:1 and 30:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 100:1 and 40:1. In some embodiments, the
composition comprises a molar ratio of meglumine, histidine (or
mixture thereof) to linaclotide between 100:1 and 50:1. In some
embodiments, the composition comprises a molar ratio of meglumine,
histidine (or mixture thereof) to linaclotide between 100:1 and
60:1. In some embodiments, the composition comprises a molar ratio
of meglumine, histidine (or mixture thereof) to linaclotide between
100:1 and 70:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide of at least 5:1. In some embodiments, the composition
comprises a molar ratio of meglumine, histidine (or mixture
thereof) to linaclotide of at least 10:1. In some embodiments, the
composition comprises a molar ratio of meglumine, histidine (or
mixture thereof) to linaclotide of at least 20:1. In some
embodiments, the composition comprises a molar ratio of meglumine,
histidine (or mixture thereof) to linaclotide of at least 25:1. In
some embodiments, the composition comprises a molar ratio of
meglumine, histidine (or mixture thereof) to linaclotide of at
least 30:1. In some embodiments, the composition comprises a molar
ratio of meglumine, histidine (or mixture thereof) to linaclotide
of at least 40:1.
[0032] In some embodiments, the pharmaceutical composition (e.g.,
capsule, tablet, bead or granule) comprises a molar ratio of
meglumine, histidine (or mixture thereof) (e.g., an amine such as
histidine or meglumine) to linaclotide between 200:1 and 1:1. In
some embodiments, the composition comprises a molar ratio of
meglumine, histidine (or mixture thereof) to linaclotide between
175:1 and 10:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 160:1 and 30:1. In some embodiments, the
composition comprises a molar ratio of meglumine, histidine (or
mixture thereof) to linaclotide between 150:1 and 50:1. In some
embodiments, the composition comprises a molar ratio of meglumine,
histidine (or mixture thereof) to linaclotide between 125:1 and
75:1. In some embodiments, the composition comprises a molar ratio
of meglumine, histidine (or mixture thereof) to linaclotide between
120:1 and 80:1. In some embodiments, the composition comprises a
molar ratio of meglumine, histidine (or mixture thereof) to
linaclotide between 110:1 and 90:1.
[0033] In some embodiments, the composition (e.g., bead) comprises
0.00001 to 1% by weight of histidine. In some embodiments, the
composition comprises 0.0001 to 0.5% by weight of histidine. In
some embodiments, the composition comprises 0.0001 to 0.3% by
weight of histidine (for example, 0.0001 to 0.1% by weight, 0.001
to 0.07 wt. %, 0.005 to 0.05 wt. %, 0.005 to 0.04 wt. %, 0.008 to
0.03 wt. %, 0.008 to 0.02 wt. %, 0.008 to 0.015 wt. %, 0.008 to
0.012 wt. %, or even about 0.01% by weight of histidine).
[0034] In some embodiments, the composition (e.g., bead or granule)
comprises 0.00001 to 1% by weight of meglumine. In some
embodiments, the composition comprises 0.0001 to 0.5% by weight of
meglumine. In some embodiments, the composition comprises 0.0001 to
0.3% by weight of meglumine (for example, 0.0001 to 0.1% by weight,
0.001 to 0.07 wt. %, 0.005 to 0.05 wt. %, 0.005 to 0.04 wt. %,
0.008 to 0.03 wt. %, 0.008 to 0.02 wt. %, 0.008 to 0.015 wt. %,
0.008 to 0.012 wt. %, or even about 0.01% by weight of
meglumine).
[0035] In some embodiments, the pharmaceutical composition
comprises melamine, gelatin, glycine, glycine-leucine, albumin or
asparagine in place of, or in combination with, the meglumine,
histidine (or mixture thereof) component. The melamine, gelatin,
glycine, glycine-leucine, albumin or asparagine can be included in
the composition in any desired amount, such as at the same
concentration or in the same molar ratios disclosed herein with
respect to the meglumine and histidine component.
[0036] The pharmaceutical composition can comprise any suitable
cation(s) or pharmaceutically acceptable salt thereof. Suitable
cations include, for example, metal or organic cations. In some
embodiments, the composition comprises a metal cation selected from
calcium, potassium, magnesium, zinc, aluminum, iron, tin,
manganese, chromium, cobalt, nickel, barium, sodium, or a
combination or mixture thereof. In some embodiments, the
composition comprises a metal cation selected from calcium,
potassium, magnesium, zinc, aluminum, manganese, chromium, cobalt,
nickel, barium, sodium, or a combination or mixture thereof. In
some embodiments, the composition comprises a metal cation selected
from aluminum, calcium, potassium, sodium, magnesium, manganese,
zinc, or a combination or mixture thereof. In some embodiments, the
composition comprises a metal cation selected from calcium,
magnesium, manganese, zinc, or a combination or mixture thereof. In
some embodiments, the composition comprises a divalent metal
cation. In some embodiments, the composition comprises a divalent
metal cation selected from Ca.sup.2+, Mg.sup.2+, Zn.sup.2+,
Mn.sup.2+, or a combination or mixture thereof. In some
embodiments, the composition comprises Mg.sup.2+. In some
embodiments, the composition comprises Ca.sup.2+. In some
embodiments, the composition comprises Zn.sup.2+. In some
embodiments, the composition comprises aluminum.
[0037] The cation can be added to the composition in any suitable
form, for example any pharmaceutically acceptable salt with any
appropriate counterion. Suitable metal salts include, for example,
calcium chloride, calcium carbonate, calcium acetate, magnesium
chloride, magnesium acetate, zinc acetate, zinc chloride, aluminum
chorlide or mixtures thereof. In some embodiments, the composition
comprises calcium chloride, magnesium chloride, zinc acetate, or a
combination or mixture thereof. In some embodiments, the
composition comprises calcium chloride. In some embodiments, the
composition comprises magnesium chloride. In some embodiments, the
composition comprises zinc acetate.
[0038] Suitable organic cations include, for example, ammonium
hydroxide, D-arginine, L-arginine, t-butylamine, calcium acetate
hydrate, calcium carbonate, calcium DL-malate, calcium hydroxide,
choline, ethanolamine, ethylenediamine, glycine, L-histidine,
L-lysine, magnesium hydroxide, N-methyl-D-glucamine, L-ornithine
hydrochloride, potassium hydroxide, procaine hydrochloride,
L-proline, pyridoxine, L-serine, sodium hydroxide, DL-tryptophan,
tromethamine, L-tyrosine, L-valine, carnitine, taurine, creatine
malate, arginine alpha keto glutarate, ornithine alpha keto
glutarate, spermine acetate, spermidine chloride, or combinations
or mixtures thereof. In some embodiments, the organic cation is
selected from the group consisting of N-methyl D-glucamine,
choline, arginine, lysine, procaine, tromethamine (TRIS), spermine,
N-methyl-morpholine, glucosamine, N,N-bis 2-hydroxyethyl glycine,
diazabicycloundecene, creatine, arginine ethyl ester, amantadine,
rimantadine, ornithine, taurine, citrulline, or a combination or
mixture thereof.
[0039] The pharmaceutical composition can comprise any stabilizing
amount of a cation. In some embodiments, the pharmaceutical
composition comprises a molar ratio of cation (e.g., Ca.sup.2+ or a
salt thereof) to linaclotide between 200:1 and 1:1. In some
embodiments, the composition comprises a molar ratio of cation
(e.g., Ca.sup.2+ or a salt thereof) to linaclotide between 175:1
and 10:1. In some embodiments, the composition comprises a molar
ratio of cation (e.g., Ca.sup.2+ or a salt thereof) to linaclotide
between 160:1 and 30:1. In some embodiments, the composition
comprises a molar ratio of cation (e.g., Ca.sup.2+ or a salt
thereof) to linaclotide between 150:1 and 50:1. In some
embodiments, the composition comprises a molar ratio of cation
(e.g., Ca.sup.2+ or a salt thereof) to linaclotide between 125:1
and 75:1. In some embodiments, the composition comprises a molar
ratio of cation (e.g., Ca.sup.2+ or a salt thereof) to linaclotide
between 120:1 and 80:1. In some embodiments, the composition
comprises a molar ratio of cation (e.g., Ca.sup.2+ or a salt
thereof) to linaclotide between 110:1 and 90:1.
[0040] In some embodiments, the composition (e.g., bead or granule)
comprises 0.0001 to 2% by weight of Ca.sup.2+ or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises 0.0005 to 1.5 wt. % of Ca.sup.2+ or a salt thereof. In
some embodiments, the composition comprises 0.001 to 1 wt. % (e.g.,
0.01 to 0.75 wt. %, 0.05 to 0.5 wt. %, 0.05 to 0.3 wt. %, 0.05 to
0.2 wt. %, 0.07 to 0.15 wt. %, or even about 0.1% by weight) of
Ca.sup.2+ or a salt thereof.
[0041] In some embodiments, the pharmaceutical composition
comprises a molar ratio of cation to linaclotide between 100:1 and
1:100. In some embodiments, the composition comprises a molar ratio
of cation to linaclotide between 100:1 and 1:1. In some
embodiments, the composition comprises a molar ratio of cation to
linaclotide between 90:1 and 2:1. In some embodiments, the
composition comprises a molar ratio of cation to linaclotide
between 80:1 and 5:1. In some embodiments, the composition
comprises a molar ratio of cation to linaclotide between 70:1 and
10:1. In some embodiments, the composition comprises a molar ratio
of cation to linaclotide between 60:1 and 20:1. In some
embodiments, the composition comprises a molar ratio of cation to
linaclotide between 50:1 and 30:1. In some embodiments, the
composition comprises a molar ratio of cation to linaclotide
between 40:1 and 20:1. In some embodiments, the composition
comprises a molar ratio of cation to linaclotide between 100:1 and
20:1. In some embodiments, the composition comprises a molar ratio
of cation to linaclotide between 100:1 and 25:1. In some
embodiments, the composition comprises a molar ratio of cation to
linaclotide between 100:1 and 30:1. In some embodiments, the
composition comprises a molar ratio of cation to linaclotide
between 100:1 and 40:1. In some embodiments, the composition
comprises a molar ratio of cation to linaclotide between 100:1 and
50:1. In some embodiments, the composition comprises a molar ratio
of cation to linaclotide between 100:1 and 60:1. In some
embodiments, the composition comprises a molar ratio of cation to
linaclotide between 100:1 and 70:1. In some embodiments, the
composition comprises a molar ratio of cation to linaclotide of at
least 5:1. In some embodiments, the composition comprises a molar
ratio of cation to linaclotide of at least 10:1. In some
embodiments, the composition comprises a molar ratio of cation to
linaclotide of at least 20:1. In some embodiments, the composition
comprises a molar ratio of cation to linaclotide of at least 25:1.
In some embodiments, the composition comprises a molar ratio of
cation to linaclotide of at least 30:1. In some embodiments, the
composition comprises a molar ratio of cation to linaclotide of at
least 40:1. In some embodiments, the composition comprises a molar
ratio of cation to linaclotide of at least 60:1.
[0042] The pharmaceutical composition can comprise any suitable
polymer. Suitable polymers include, for example, polyvinyl
pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxylpropyl methyl
cellulose (HPMC), hydroxylpropyl cellulose (HPC), methyl cellulose,
methacrylate polymers, cyclodextrin, dextrin, dextran, polyacrylic
acid, chitosan, guar gum, xanthan gum, polyethylene oxide (e.g.,
polyethylene polypropylene oxide), poly (sodium vinylsulfonate),
polyethylene glycol, poly(arginine), poly carbophil, polyvinyl
pyrrolidone-co-vinyl acetate, a poloxamer (e.g., Pluronic.RTM.
products available from BASF), alginate, trehalose, sucrose,
inulin, or a combination or mixture thereof. In some embodiments,
the composition comprises a polymer selected from PVP, PVA,
methacrylate polymers, cyclodextrin, dextran, polyacrylic acid,
chitosan, guar gum, xanthan gum, polyethylene oxide, polyethylene
glycol, poly(arginine), poly carbophil, polyvinyl
pyrrolidone-co-vinyl acetate, a poloxamer, or a combination or
mixture thereof. In some embodiments, the composition comprises
PVP, PVA, polyethylene oxide, or a mixture thereof. In some
embodiments, the composition comprises PVP, PVA, or a mixture
thereof. In some embodiments, the composition comprises PVP. In
some embodiments, the composition comprises PVA.
[0043] The composition can contain any suitable amount of a
polymer. In some embodiments, the composition (e.g., bead or
granule) comprises 0.1 to 10% by weight of a polymer (for example,
PVA or PVP). In some embodiments, the composition comprises 1 to 5
wt. % of a polymer component. In some embodiments, the composition
comprises 2 to 5 wt. % (e.g., 3 to 5 wt. %, 3.5 to 4.5 wt. %, or
about 4% by weight) of a polymer (e.g., PVA or PVP).
[0044] In some embodiments, the pharmaceutical composition
comprises PVP and a stabilizing amount of an amino acid selected
from meglumine, histidine or a mixture thereof. In some
embodiments, the composition comprises PVP and a stabilizing amount
of histidine. In some embodiments, the composition comprises PVP
and a stabilizing amount of meglumine.
[0045] In some embodiments, the pharmaceutical composition
comprises PVA and an amino acid selected from meglumine, histidine
or a mixture thereof. In some embodiments, the composition
comprises PVA and histidine. In some embodiments, the composition
comprises PVA and meglumine.
[0046] In some embodiments, the pharmaceutical composition
comprises a stabilizing amount of an amino acid selected from
histidine, meglumine and combinations thereof; and a stabilizing
amount of a cation (e.g., a metal cation, for example, a divalent
metal cation selected from Mg.sup.2+, Ca.sup.2+, Zn.sup.2+ or a
salt thereof or a combination or mixture thereof). In some
embodiments, the composition comprises a stabilizing amount of an
amino acid selected from histidine, meglumine and combinations
thereof; and a stabilizing amount of a divalent metal cation
selected from Mg.sup.2+, Ca.sup.2+ or a salt thereof or a
combination or mixture thereof. In some embodiments, the
composition comprises a stabilizing amount of histidine, meglumine
or a mixture thereof; and a divalent metal cation selected from
Ca.sup.2+, Zn.sup.2+ or a salt thereof or a combination or mixture
thereof. In some embodiments, the composition comprises a
stabilizing amount of meglumine and a stabilizing amount of
Ca.sup.2+ or a salt thereof. In some embodiments, the composition
comprises a stabilizing amount of histidine and a stabilizing
amount of Ca.sup.2+ or a salt thereof. In some embodiments, the
composition comprises a cation and amino acid (e.g., meglumine,
histidine or mixture thereof) in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) between 2:1 and
1:2. In some embodiments, the composition comprises a cation and
amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) between 1.75:1 and 1:1.75. In some
embodiments, the composition comprises a cation and amino acid
(e.g., meglumine, histidine or mixture thereof) in a molar ratio of
cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) between 1.5:1 and 1:1.5. In some embodiments,
the composition comprises a cation and amino acid (e.g., meglumine,
histidine or mixture thereof) in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) between 1.25:1
and 1:1.25. In some embodiments, the composition comprises a cation
and amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) between 1.1:1 and 1:1.1.
[0047] In some embodiments, the composition comprises a cation and
amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) of less than 5:1. In some embodiments, the
composition comprises a cation and amino acid (e.g., meglumine,
histidine or mixture thereof) in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) of less than
4:1. In some embodiments, the composition comprises a cation and
amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) of less than 3:1. In some embodiments, the
composition comprises a cation and amino acid (e.g., meglumine,
histidine or mixture thereof) in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) of less than
2:1. In some embodiments, the composition comprises a cation and
amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) of less than 1.75:1. In some embodiments, the
composition comprises a cation and amino acid (e.g., meglumine,
histidine or mixture thereof) in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) of less than
1.5:1. In some embodiments, the composition comprises a cation and
amino acid (e.g., meglumine, histidine or mixture thereof) in a
molar ratio of cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) of less than 1.25:1.
[0048] In some preferred embodiments, the composition comprises a
cation (e.g., Ca.sup.2+) and an amino acid selected from meglumine,
histidine or mixture thereof in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) between about
1.5:1 and 0.5:1. In some preferred embodiments, the composition
comprises a cation (e.g., Ca.sup.2+) and an amino acid selected
from meglumine, histidine or mixture thereof in a molar ratio of
cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) between about 1.4:1 and 0.6:1. In some
preferred embodiments, the composition comprises a cation (e.g.,
Ca.sup.2+) and an amino acid selected from meglumine, histidine or
mixture thereof in a molar ratio of cation:amino acid (e.g.,
Ca.sup.2+:meglumine or Ca.sup.2+:histidine) between about 1.3:1 and
0.7:1. In some preferred embodiments, the composition comprises a
cation (e.g., Ca.sup.2+) and an amino acid selected from meglumine,
histidine or mixture thereof in a molar ratio of cation:amino acid
(e.g., Ca.sup.2+:meglumine or Ca.sup.2+:histidine) between about
1.2:1 and 0.8:1. In some preferred embodiments, the composition
comprises a cation (e.g., Ca.sup.2+) and an amino acid selected
from meglumine, histidine or mixture thereof in a molar ratio of
cation:amino acid (e.g., Ca.sup.2+:meglumine or
Ca.sup.2+:histidine) between about 1.1:1 and 0.9:1.
[0049] In some embodiments, the pharmaceutical composition
comprises (i) a polymer (e.g., PVP or PVA), (ii) a stabilizing
amount of meglumine, histidine or a combination thereof, and (iii)
a stabilizing amount of a cation (e.g., a divalent metal cation for
example Mg.sup.2+, Ca.sup.2+, Zn.sup.2+ or a
pharmaceutically-acceptable salt thereof or a combination or
mixture thereof). In some embodiments, the pharmaceutical
composition comprises (i) a polymer (e.g., PVP and/or PVA), (ii)
histidine or meglumine, and (iii) Mg.sup.2+, Ca.sup.2+, Zn.sup.2+
or a salt thereof or a combination or mixture thereof. In some
embodiments, the composition comprises a stabilizing amount of PVA
and stabilizing amounts of meglumine, and a metal cation.
[0050] In some embodiments, the pharmaceutical composition (e.g.,
bead or granule) comprises linaclotide (e.g., a therapeutically
effective amount of linaclotide, for example, between 0.01 .mu.g
and 300 .mu.g, between 0.01 .mu.g and 150 .mu.g, or between 0.01
.mu.g and 125 .mu.g of linaclotide), histidine in a molar ratio to
linaclotide between 150:1 and 50:1 (e.g., between 125:1 and 75:1,
between 120:1 and 80:1, between 110:1 and 90:1 or a molar ratio of
histidine to linaclotide of about 100:1), Ca.sup.2+ or a salt
thereof in a molar ratio to linaclotide between 150:1 and 50:1
(e.g., between 125:1 and 75:1, between 120:1 and 80:1, between
110:1 and 90:1 or a molar ratio of Ca.sup.2+ or a salt thereof to
linaclotide of about 100:1) and optionally a polymer (e.g., PVA or
PVP).
[0051] In some embodiments, the pharmaceutical composition (e.g.,
bead or granule) comprises linaclotide (e.g., a therapeutically
effective amount of linaclotide, for example, between 0.01 .mu.g
and 300 .mu.g, between 0.01 .mu.g and 150 .mu.g, or between 0.01
.mu.g and 125 .mu.g of linaclotide), meglumine in a molar ratio to
linaclotide between 150:1 and 50:1 (e.g., between 125:1 and 75:1,
between 120:1 and 80:1, between 110:1 and 90:1 or even a molar
ratio of meglumine to linaclotide of about 100:1), Ca.sup.2+ or a
salt thereof in a molar ratio to linaclotide between 150:1 and 50:1
(e.g., between 125:1 and 75:1, between 120:1 and 80:1, between
110:1 and 90:1 or a molar ratio of Ca.sup.2+ or a salt thereof to
linaclotide of about 100:1) and optionally a polymer (e.g., PVA or
PVP).
[0052] In some embodiments, the composition (e.g., bead or granule)
comprises linaclotide (e.g., a therapeutically effective amount of
linaclotide, for example, between 0.01 .mu.g and 300 .mu.g, between
0.01 .mu.g and 150 .mu.g, or between 0.01 .mu.g and 125 .mu.g of
linaclotide), an amino acid (e.g., meglumine or histidine) in a
concentration of 0.005 to 0.05% by weight (e.g., 0.005 to 0.04 wt.
%, 0.008 to 0.03 wt. %, 0.008 to 0.02 wt. %, 0.008 to 0.015 wt. %,
0.008 to 0.012 wt. %, or even about 0.01 wt. %), a metal cation
(e.g., Ca.sup.2+ or a salt thereof) in a concentration of 0.01 to
0.75% by weight (e.g., 0.05 to 0.5 wt. %, 0.05 to 0.3 wt. %, 0.05
to 0.2 wt. %, 0.07 to 0.15 wt. %, or even about 0.1% by weight) and
optionally a polymer (e.g., PVA or PVP).
[0053] In some embodiments, the composition (e.g., bead or granule)
comprises linaclotide (e.g., a therapeutically effective amount of
linaclotide, for example, between 0.01 .mu.g and 300 .mu.g, between
0.01 .mu.g and 150 .mu.g, or between 0.01 .mu.g and 125 .mu.g of
linaclotide), meglumine in a concentration of 0.005 to 0.05% by
weight (e.g., 0.005 to 0.04 wt. %, 0.008 to 0.03 wt. %, 0.008 to
0.02 wt. %, 0.008 to 0.015 wt. %, 0.008 to 0.012 wt. %, or even
about 0.01 wt. %), Ca.sup.2+ or a salt thereof in a concentration
of 0.01 to 0.75% by weight (e.g., 0.05 to 0.5 wt. %, 0.05 to 0.3
wt. %, 0.05 to 0.2 wt. %, 0.07 to 0.15 wt. %, or even about 0.1% by
weight) and optionally a polymer (e.g., PVA or PVP).
[0054] In some embodiments, the composition (e.g., bead or granule)
comprises linaclotide (e.g., a therapeutically effective amount of
linaclotide, for example, between 0.01 .mu.g and 300 .mu.g, between
0.01 .mu.g and 150 .mu.g, or between 0.01 .mu.g and 125 .mu.g of
linaclotide), histidine in a concentration of 0.005 to 0.05% by
weight (e.g., 0.005 to 0.04 wt. %, 0.008 to 0.03 wt. %, 0.008 to
0.02 wt. %, 0.008 to 0.015 wt. %, 0.008 to 0.012 wt. %, or even
about 0.01 wt. %), Ca.sup.2+ or a salt thereof in a concentration
of 0.01 to 0.75% by weight (e.g., 0.05 to 0.5 wt. %, 0.05 to 0.3
wt. %, 0.05 to 0.2 wt. %, 0.07 to 0.15 wt. %, or even about 0.1% by
weight) and optionally a polymer (e.g., PVA or PVP).
[0055] The pharmaceutical composition may also comprise any one or
more filling agents. Suitable filling agents include, but are not
limited to, starch, calcium carbonate, calcium sulfate,
hydroxylpropylmethyl cellulose, fructose, methyl cellulose,
dextrates, dextrose, dextran, lactitol, maltose, sucrose, sorbitol,
isomalt, pregelatinized starch, dicalcium phosphate,
microcrystalline cellulose, mannitol, gelatin, trehalose,
erythitol, maltitol, lactose, glucose, or a combination thereof, or
a mixture thereof In some embodiments, the filling agent is
isomalt. In some embodiments, the filling agent is gelatin. In some
embodiments, the filling agent is mannitol. In some embodiments,
the filling agent is pregelatinized starch. In some embodiments,
the filling agent is microcrystalline cellulose.
[0056] The pharmaceutical composition can comprise any suitable
concentration of filling agent. In some embodiments, for example,
the composition comprises one or more filling agents in a
concentration of 0.1-99% by weight, relative to the total weight of
the composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 1-95 wt.
% of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 10-90
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 20-90
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 25-85
wt. % of filling agent(s), relative to the total weight of the
composition. some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 30-80
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 40-70
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 10-60
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, for example, the composition
comprises one or more filling agents in a concentration of 20-50
wt. % of filling agent(s), relative to the total weight of the
composition. In some embodiments, the composition comprises one or
more filling agents in a concentration of at least 20 wt. %, for
example, at least 40 wt. %, at least 60 wt. %, at least 70 wt. %,
at least 80 wt. %, or at least 90 wt. %, relative to the total
weight of the composition.
[0057] In some embodiments, the pharmaceutical composition (e.g.,
orally disintegrating composition) can comprise one or more
plasticizers. Suitable plasticizers include, but are not limited
to, polyethylene glycol, propylene glycol, glycerin, glycerol,
monoacetin, diacetin, triacetin, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, dibutyl sebacate, triethyl titrate,
tributyl citrate, triethyl citrate, triethyl acetyl citrate, castor
oil, acetylated monoglycerides, sorbitol or combinations thereof In
exemplary embodiments, the concentration of the plasticizer in the
formulation may be about 0 to about 30 wt %, for example, about 1
to about 20 wt %, about 0.1 to about 10 wt %, about 1 to about 5 wt
%, or even 0.1 to about 4 wt %.
[0058] In some embodiments, the pharmaceutical composition is an
orally-disintegrating composition and comprises a film-forming
agent, a water-soluble polymer, a combination of two or more
water-soluble polymers or a combination of a water-soluble polymer
and a water-insoluble or poorly-soluble polymer. Water-soluble
polymers that may be used in the orally-dissolving formulations of
the present invention include, but are not limited to, cellulose
derivatives, synthetic polymers polyacrylates and natural gums. For
example, the water-soluble polymers used in the orally-dissolving
formulations of the present invention may include, but are not
limited to, methyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, ethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, carboxymethyl cellulose,
cellulose acetate phthalate, cellulose acetate butyrate, amylose,
dextran, casein, pullulan, gelatin, pectin, agar, carrageenan,
xanthan gum, tragacanth, guar gum, acacia gum, arabic gum,
polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone,
polyvinyl alcohol, cyclodextrin, carboxyvinyl polymers, sodium
alginate, polyacrylic acid, methylmethacrylate or mixtures thereof
In exemplary embodiments, the concentration of the water-soluble
polymer in the formulation may be about 20% to about 90% (by
weight), preferably between about 40% to about 80% (by weight).
[0059] One skilled in the art, with the benefit of this disclosure,
will understand that other components may be included to enhance
one or more properties of the pharmaceutical compositions. In some
embodiments, for example, the pharmaceutical composition may
include one or more disintegrants, lubricants, anti-caking
additives, anti-microbial agents, antifoaming agents, emulsifiers,
surfactants, buffering agents, and/or coloring agents.
[0060] Suitable disintegrants include, for example, agar-agar,
calcium carbonate, microcrystalline cellulose, croscarmellose
sodium, crospovidone, povidone, polacrilin potassium, sodium starch
glycolate, potato or tapioca starch, other starches,
pre-gelatinized starch, clays, other algins, other celluloses,
gums, and mixtures thereof In some embodiments, the disintegrant is
crospovidone. In some embodiments, the disintegrant is
croscarmellose sodium.
[0061] Suitable lubricants include, for example, calcium stearate,
magnesium stearate, mineral oil, light mineral oil, glycerin,
sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl
laurate, agar, syloid silica gel (AEROSIL 200, W. R. Grace Co.,
Baltimore, Md. USA), a coagulated aerosol of synthetic silica
(Evonik Degussa Co., Plano, Tex. USA), a pyrogenic silicon dioxide
(CAB-O-SIL, Cabot Co., Boston, Mass. USA), and mixtures
thereof.
[0062] Suitable anti-caking additives include, for example, calcium
silicate, magnesium silicate, silicon dioxide, colloidal silicon
dioxide, talc, and mixtures thereof. In some embodiments, the
composition comprises about 0.01 wt. % to about 5 wt. % of an
anti-caking additive (e.g., talc). In some embodiments, the
composition comprises about 0.05 wt. % to about 2 wt. % of an
anti-caking additive (e.g., talc). In some embodiments, the
composition comprises about 0.1 wt. % to about 1 wt. % of an
anti-caking additive (e.g., talc). In some embodiments, the
composition comprises about 0.25 wt. % to about 0.75 wt. % (e.g.,
about 0.5 wt. %) of an anti-caking additive (e.g., talc).
[0063] Suitable anti-microbial additives that may be used, e.g., as
a preservative for the linaclotide compositions, include, for
example, benzalkonium chloride, benzethonium chloride, benzoic
acid, benzyl alcohol, butyl paraben, cetylpyridinium chloride,
cresol, chlorobutanol, dehydroacetic acid, ethylparaben,
methylparaben, phenol, phenylethyl alcohol, phenoxyethanol,
phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate,
propylparaben, sodium benzoate, sodium dehydroacetate, sodium
propionate, sorbic acid, thimersol, thymo, and mixtures
thereof.
[0064] In some embodiments, the pharmaceutical composition (e.g.,
orally-disintegrating composition) may comprise a taste-masking
agent. Generally, any natural or synthetic flavoring agent or
sweetening agent known in the art may be used in the pharmaceutical
compositions of the present invention. For example, suitable
taste-masking agents include, but are not limited to, essential
oils, water-soluble extracts, sugar, monosaccharides,
oligosaccharides, aldose, ketose, dextrose, maltose, lactose,
glucose, fructose, sucrose, mannitol xylitol, D-sorbitol,
erythritol, pentitol, hexitol, malitol, acesulfame potassium,
talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium
saccharin, sodium cyclamate, eugenyl formate aldehyde flavorings
and combinations thereof.
[0065] Exemplary aldehyde flavorings that may be used include, but
are not limited to acetaldehyde (apple); benzaldehyde (cherry,
almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral
(lemon, lime); neral, i.e., beta citral (lemon, lime); decanal
(orange, lemon); ethyl vanillin (vanilla, cream); heliotropine,
i.e., piperonal (vanilla, cream); vanillin (vanilla, cream);
[0066] alpha-amyl cinnamaldehyde (spicy fruity flavors);
butyraldehyde (butter, cheese); valeraldehyde (butter, cheese);
citronellal (modifies, many types); decanal (citrus fruits);
aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits);
aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry
fruits); hexenal, i.e., trans-2 (berry fruits); tolyl aldehyde
(cherry, almond); veratraldehyde (vanilla);
2,6-dimethyl-5-heptenal, i.e., melonal (melon); 2-6-dimethyloctanal
(green fruit); and 2-dodecenal (citrus, mandarin). In some
embodiments, the taste-masking agents may include combination of
acesulfame potassium and flavors. One skilled in the art with the
benefit of the present disclosure will appreciate that other and
further ingredients may be included in the pharmaceutical
composition of the present invention, for example, a matrix-forming
polymer permeation enhancer, substance for imparting mucoadhesive
properties, or other auxiliary substances.
[0067] The composition may also comprise any suitable
pharmaceutically acceptable carrier or medium. Suitable
pharmaceutically acceptable carriers include, for example, any
solvents, dispersants, pH-buffering agents, coatings,
absorption-promoting agents, controlled-release agents, and one or
more inert excipients (e.g., filling agents, starches, polyols,
granulating agents, microcrystalline cellulose, diluents,
lubricants, binders, disintegrating agents), or the like. In
addition, the compositions can contain any desired additional
components, additives, and/or species, for example, surface active
additives, dispersing additives, humectants, suspending agents,
solubilizers, buffering agents, disintegrants, preservatives,
colorants, flavorants, and the like. In some embodiments, the
composition comprises one or more ion species that interact with
linaclotide.
[0068] The composition can also comprise any suitable pH buffering
agent. In some embodiments, the pH buffering agent is present in
the composition in an amount sufficient to achieve the isoelectric
point of linaclotide. In the regard, the composition can have any
desired pH. In some embodiments, the composition has a pH of 2 to 5
(for example, a pH of 2 to 4.5, a pH of 2 4o 4, a pH of 2.5 to 4, a
pH of 2.5 to 3.5, a pH of 2.5 to 3, or even a pH of 3).
[0069] In some embodiments, the composition comprises linaclotide
and a hydrolysis product, e.g., a hydrolysis product comprising or
having a structure of:
##STR00001##
[0070] The composition can contain any desired concentration of the
hydrolysis product. In some embodiments, the composition comprises
less than 10 wt. % of the hydrolysis product. In some embodiments,
the composition comprises less than 7 wt. % of the hydrolysis
product. In some embodiments, the composition comprises less than 6
wt. % of the hydrolysis product. In some embodiments, the
composition comprises less than 5 wt. % of the hydrolysis product.
In some embodiments, the composition comprises less than 4 wt. % of
the hydrolysis product. In some embodiments, the composition
comprises less than 3 wt. % of the hydrolysis product. In some
embodiments, the composition comprises less than 2 wt. % of the
hydrolysis product. In some embodiments, the composition comprises
less than 1 wt. % of the hydrolysis product. In some embodiments,
the composition comprises between 0.01 and 10 wt. % of the
hydrolysis product. In some embodiments, the composition comprises
between 0.1 and 7 wt. % of the hydrolysis product. In some
embodiments, the composition comprises between 0.1 and 5 wt. % of
the hydrolysis product. In some embodiments, the composition
comprises between 0.5 and 5 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 1 and 5 wt. %
of the hydrolysis product. In some embodiments, the composition
comprises between 0.1 and 4 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 0.5 and 4 wt. %
of the hydrolysis product. In some embodiments, the composition
comprises between 1 and 4 wt. % of the hydrolysis product. In some
embodiments, the composition comprises between 0.1 and 3 wt. % of
the hydrolysis product. In some embodiments, the composition
comprises between 0.5 and 3 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 1 and 3 wt. %
of the hydrolysis product. In some embodiments, the composition
comprises between 0.1 and 2.5 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 0.5 and 2.5 wt.
% of the hydrolysis product. In some embodiments, the composition
comprises between 1 and 2.5 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 0.1 and 2 wt. %
of the hydrolysis product. In some embodiments, the composition
comprises between 0.5 and 2 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 1 and 2 wt. %
of the hydrolysis product. In some embodiments, the composition
comprises between 0.1 and 1.5 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 0.5 and 1.5 wt.
% of the hydrolysis product. In some embodiments, the composition
comprises between 0.1 and 1 wt. % of the hydrolysis product. In
some embodiments, the composition comprises between 0.5 and 1 wt. %
of the hydrolysis product.
[0071] In some embodiments, the composition comprises linaclotide
and a formaldehyde imine product, e.g., a formaldehyde imine
product comprising or having a structure of:
##STR00002##
[0072] The composition can contain any desired concentration of the
formaldehyde imine product. In some embodiments, the composition
comprises less than 10 wt. % of the formaldehyde imine product. In
some embodiments, the composition comprises less than 7 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises less than 6 wt. % of the formaldehyde imine
product. In some embodiments, the composition comprises less than 5
wt. % of the formaldehyde imine product. In some embodiments, the
composition comprises less than 4 wt. % of the formaldehyde imine
product. In some embodiments, the composition comprises less than 3
wt. % of the formaldehyde imine product. In some embodiments, the
composition comprises less than 2 wt. % of the formaldehyde imine
product. In some embodiments, the composition comprises less than 1
wt. % of the formaldehyde imine product. In some embodiments, the
composition comprises between 0.01 and 10 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 0.1 and 7 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 5 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 5 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 1 and 5 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 4 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 4 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 1 and 4 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 3 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 3 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 1 and 3 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 2.5 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 2.5 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 1 and 2.5 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 2 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 2 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 1 and 2 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.1 and 1.5 wt. % of
the formaldehyde imine product. In some embodiments, the
composition comprises between 0.5 and 1.5 wt. % of the formaldehyde
imine product. In some embodiments, the composition comprises
between 0.1 and 1 wt. % of the formaldehyde imine product. In some
embodiments, the composition comprises between 0.5 and 1 wt. % of
the formaldehyde imine product.
[0073] In some embodiments, the composition comprises linaclotide
and a peptide modified with the addition of methylene at the
.alpha.-amine group of the N-terminal Cys.sub.1that is cross-linked
to the amine group of Cys.sub.2 to form an imidazolidinone 5
membered ring at the N-terminus of the peptide ("Cys.sub.1-IMD
product") comprising or having a structure of:
##STR00003##
[0074] The composition can contain any desired concentration of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises less than 10 wt. % of the Cys.sub.1-IMD product. In some
embodiments, the composition comprises less than 7 wt. % of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises less than 6 wt. % of the Cys.sub.1-IMD product. In some
embodiments, the composition comprises less than 5 wt. % of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises less than 4 wt. % of the Cys.sub.1-IMD product. In some
embodiments, the composition comprises less than 3 wt. % of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises less than 2 wt. % of the Cys.sub.1-IMD product. In some
embodiments, the composition comprises less than 1 wt. % of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises between 0.01 and 10 wt. % of the Cys.sub.1-IMD product.
In some embodiments, the composition comprises between 0.1 and 7
wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 0.1 and 5 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 0.5
and 5 wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 1 and 5 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 0.1
and 4 wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 0.5 and 4 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 1
and 4 wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 0.1 and 3 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 0.5
and 3 wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 1 and 3 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 0.1
and 2.5 wt. % of the Cys.sub.1-IMD product. In some embodiments,
the composition comprises between 0.5 and 2.5 wt. % of the
Cys.sub.1-IMD product. In some embodiments, the composition
comprises between 1 and 2.5 wt. % of the Cys.sub.1-IMD product. In
some embodiments, the composition comprises between 0.1 and 2 wt. %
of the Cys.sub.1-IMD product In some embodiments, the composition
comprises between 0.5 and 2 wt. % of the Cys.sub.1-IMD product. In
some embodiments, the composition comprises between 1 and 2 wt. %
of the Cys.sub.1-IMD product. In some embodiments, the composition
comprises between 0.1 and 1.5 wt. % of the Cys.sub.1-IMD product.
In some embodiments, the composition comprises between 0.5 and 1.5
wt. % of the Cys.sub.1-IMD product. In some embodiments, the
composition comprises between 0.1 and 1 wt. % of the Cys.sub.1-IMD
product. In some embodiments, the composition comprises between 0.5
and 1 wt. % of the Cys.sub.1-IMD product.
[0075] In some embodiments, the composition comprises linaclotide
and an oxidation product, e.g., an oxidation product comprising or
having a structure of:
##STR00004##
[0076] Alternatively, or in addition, the composition comprises
linaclotide and an oxidation product having the depicted structure
but wherein oxidation occurs at any one or more of the six depicted
cysteinyl sulfurs. The composition can contain any desired
concentration of the oxidation product. In some embodiments, the
composition comprises less than 10 wt. % of the oxidation product.
In some embodiments, the composition comprises less than 7 wt. % of
the oxidation product. In some embodiments, the composition
comprises less than 6 wt. % of the oxidation product. In some
embodiments, the composition comprises less than 5 wt. % of the
oxidation product. In some embodiments, the composition comprises
less than 4 wt. % of the oxidation product. In some embodiments,
the composition comprises less than 3 wt. % of the oxidation
product. In some embodiments, the composition comprises less than 2
wt. % of the oxidation product. In some embodiments, the
composition comprises less than 1 wt. % of the oxidation product.
In some embodiments, the composition comprises between 0.01 and 10
wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.1 and 7 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.1
and 5 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.5 and 5 wt. % of the oxidation
product. In some embodiments, the composition comprises between 1
and 5 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.1 and 4 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.5
and 4 wt. % of the oxidation product. In some embodiments, the
composition comprises between 1 and 4 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.1
and 3 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.5 and 3 wt. % of the oxidation
product. In some embodiments, the composition comprises between 1
and 3 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.1 and 2.5 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.5
and 2.5 wt. % of the oxidation product. In some embodiments, the
composition comprises between 1 and 2.5 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.1
and 2 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.5 and 2 wt. % of the oxidation
product. In some embodiments, the composition comprises between 1
and 2 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.1 and 1.5 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.5
and 1.5 wt. % of the oxidation product. In some embodiments, the
composition comprises between 0.1 and 1 wt. % of the oxidation
product. In some embodiments, the composition comprises between 0.5
and 1 wt. % of the oxidation product.
[0077] In some embodiments, the composition comprises linaclotide
and an acetylation product, e.g., an acetylation product comprising
or having a structure of:
##STR00005##
[0078] The composition can contain any desired concentration of the
acetylation product. In some embodiments, the composition comprises
less than 10 wt. % of the acetylation product. In some embodiments,
the composition comprises less than 7 wt. % of the acetylation
product. In some embodiments, the composition comprises less than 6
wt. % of the acetylation product. In some embodiments, the
composition comprises less than 5 wt. % of the acetylation product.
In some embodiments, the composition comprises less than 4 wt. % of
the acetylation product. In some embodiments, the composition
comprises less than 3 wt. % of the acetylation product. In some
embodiments, the composition comprises less than 2 wt. % of the
acetylation product. In some embodiments, the composition comprises
less than 1 wt. % of the acetylation product. In some embodiments,
the composition comprises between 0.01 and 10 wt. % of the
acetylation product. In some embodiments, the composition comprises
between 0.1 and 7 wt. % of the acetylation product. In some
embodiments, the composition comprises between 0.1 and 5 wt. % of
the acetylation product. In some embodiments, the composition
comprises between 0.5 and 5 wt. % of the acetylation product. In
some embodiments, the composition comprises between 1 and 5 wt. %
of the acetylation product. In some embodiments, the composition
comprises between 0.1 and 4 wt. % of the acetylation product. In
some embodiments, the composition comprises between 0.5 and 4 wt. %
of the acetylation product. In some embodiments, the composition
comprises between 1 and 4 wt. % of the acetylation product. In some
embodiments, the composition comprises between 0.1 and 3 wt. % of
the acetylation product. In some embodiments, the composition
comprises between 0.5 and 3 wt. % of the acetylation product. In
some embodiments, the composition comprises between 1 and 3 wt. %
of the acetylation product. In some embodiments, the composition
comprises between 0.1 and 2.5 wt. % of the acetylation product. In
some embodiments, the composition comprises between 0.5 and 2.5 wt.
% of the acetylation product. In some embodiments, the composition
comprises between 1 and 2.5 wt. % of the acetylation product. In
some embodiments, the composition comprises between 0.1 and 2 wt. %
of the acetylation product. In some embodiments, the composition
comprises between 0.5 and 2 wt. % of the acetylation product. In
some embodiments, the composition comprises between 1 and 2 wt. %
of the acetylation product. In some embodiments, the composition
comprises between 0.1 and 1.5 wt. % of the acetylation product. In
some embodiments, the composition comprises between 0.5 and 1.5 wt.
% of the acetylation product. In some embodiments, the composition
comprises between 0.1 and 1 wt. % of the acetylation product. In
some embodiments, the composition comprises between 0.5 and 1 wt. %
of the acetylation product.
[0079] In some embodiments, the composition comprises linaclotide
and any desired concentration of multimers. In some embodiments,
the composition comprises less than 10 wt. % of multimer(s). In
some embodiments, the composition comprises less than 7 wt. % of
multimer(s). In some embodiments, the composition comprises less
than 6 wt. % of multimer(s). In some embodiments, the composition
comprises less than 5 wt. % of multimer(s). In some embodiments,
the composition comprises less than 4 wt. % of multimer(s). In some
embodiments, the composition comprises less than 3 wt. % of
multimer(s). In some embodiments, the composition comprises less
than 2 wt. % of multimer(s). In some embodiments, the composition
comprises less than 1 wt. % of multimer(s). In some embodiments,
the composition comprises between 0.01 and 10 wt. % of multimer(s).
In some embodiments, the composition comprises between 0.1 and 7
wt. % of multimer(s). In some embodiments, the composition
comprises between 0.1 and 5 wt. % of multimer(s). In some
embodiments, the composition comprises between 0.5 and 5 wt. % of
multimer(s). In some embodiments, the composition comprises between
1 and 5 wt. % of multimer(s). In some embodiments, the composition
comprises between 0.1 and 4 wt. % of multimer(s). In some
embodiments, the composition comprises between 0.5 and 4 wt. % of
multimer(s). In some embodiments, the composition comprises between
1 and 4 wt. % of multimer(s). In some embodiments, the composition
comprises between 0.1 and 3 wt. % of multimer(s). In some
embodiments, the composition comprises between 0.5 and 3 wt. % of
multimer(s). In some embodiments, the composition comprises between
1 and 3 wt. % of multimer(s). In some embodiments, the composition
comprises between 0.1 and 2.5 wt. % of multimer(s). In some
embodiments, the composition comprises between 0.5 and 2.5 wt. % of
multimer(s). In some embodiments, the composition comprises between
1 and 2.5 wt. % of multimer(s). In some embodiments, the
composition comprises between 0.1 and 2 wt. % of multimer(s). In
some embodiments, the composition comprises between 0.5 and 2 wt. %
of multimer(s). In some embodiments, the composition comprises
between 1 and 2 wt. % of multimer(s). In some embodiments, the
composition comprises between 0.1 and 1.5 wt. % of multimer(s). In
some embodiments, the composition comprises between 0.5 and 1.5 wt.
% of multimer(s). In some embodiments, the composition comprises
between 0.1 and 1 wt. % of multimer(s). In some embodiments, the
composition comprises between 0.5 and 1 wt. % of multimer(s).
[0080] In some embodiments, the composition comprises an effective
amount of linaclotide and any desired amount of reduced form
linaclotide. As used herein, the term "reduced form linaclotide"
refers to linaclotide having no disulfide bonds between cysteine
amino acids. In some embodiments, the composition comprises less
than 10 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises less than 7 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises less
than 6 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises less than 5 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises less
than 4 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises less than 3 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises less
than 2 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises less than 1 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.01 and 10 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 0.1 and 7 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.1 and 5 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 0.5 and 5 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
1 and 5 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises between 0. 1 and 4 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.5 and 4 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 1 and 4 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.1 and 3 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 0.5 and 3 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
1 and 3 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises between 0.1 and 2.5 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.5 and 2.5 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 1 and 2.5 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.1 and 2 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 0.5 and 2 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
1 and 2 wt. % of reduced form linaclotide. In some embodiments, the
composition comprises between 0.1 and 1.5 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.5 and 1.5 wt. % of reduced form linaclotide. In some embodiments,
the composition comprises between 0.1 and 1 wt. % of reduced form
linaclotide. In some embodiments, the composition comprises between
0.5 and 1 wt. % of reduced form linaclotide.
[0081] In some embodiments, the composition comprises an effective
amount of linaclotide and any desired amount of scrambled-form
linaclotide. As used herein, the term "scrambled-form linaclotide"
refers to linaclotide having disulfide bonds between Cys.sub.1and
Cys.sub.10, between Cys.sub.1and Cys.sub.13, between Cys.sub.1and
Cys.sub.5, between Cys.sub.1and Cys.sub.2, between Cys.sub.2 and
Cys.sub.6, between Cys.sub.2 and Cys.sub.13, between Cys.sub.2 and
Cys.sub.5, between Cys.sub.5 and Cys.sub.6, and/or between
Cys.sub.5 and Cys.sub.10 . In some embodiments, the composition
comprises less than 10 wt. % of scrambled-form linaclotide. In some
embodiments, the composition comprises less than 7 wt. % of
scrambled-form linaclotide In some embodiments, the composition
comprises less than 6 wt. % of scrambled-form linaclotide. In some
embodiments, the composition comprises less than 5 wt. % of
scrambled-form linaclotide. In some embodiments, the composition
comprises less than 4 wt. % of scrambled-form linaclotide. In some
embodiments, the composition comprises less than 3 wt. % of
scrambled-form linaclotide. In some embodiments, the composition
comprises less than 2 wt. % of scrambled-form linaclotide. In some
embodiments, the composition comprises less than 1 wt. % of
scrambled-form linaclotide. In some embodiments, the composition
comprises between 0.01 and 10 wt. % of scrambled-form linaclotide.
In some embodiments, the composition comprises between 0.1 and 7
wt. % of scrambled-form linaclotide. In some embodiments, the
composition comprises between 0.1 and 5 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
0.5 and 5 wt. % of scrambled-form linaclotide. In some embodiments,
the composition comprises between 1 and 5 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
0.1 and 4 wt. % of scrambled-form linaclotide. In some embodiments,
the composition comprises between 0.5 and 4 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
1 and 4 wt. % of scrambled-form linaclotide. In some embodiments,
the composition comprises between 0.1 and 3 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
0.5 and 3 wt. % of scrambled-form linaclotide. In some embodiments,
the composition comprises between 1 and 3 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
0.1 and 2.5 wt. % of scrambled-form linaclotide. In some
embodiments, the composition comprises between 0.5 and 2.5 wt. % of
scrambled-form linaclotide. In some embodiments, the composition
comprises between 1 and 2.5 wt. % of scrambled-form linaclotide. In
some embodiments, the composition comprises between 0.1 and 2 wt. %
of scrambled-form linaclotide. In some embodiments, the composition
comprises between 0.5 and 2 wt. % of scrambled-form linaclotide. In
some embodiments, the composition comprises between 1 and 2 wt. %
of scrambled-form linaclotide. In some embodiments, the composition
comprises between 0.1 and 1.5 wt. % of scrambled-form linaclotide.
In some embodiments, the composition comprises between 0.5 and 1.5
wt. % of scrambled-form linaclotide. In some embodiments, the
composition comprises between 0.1 and 1 wt. % of scrambled-form
linaclotide. In some embodiments, the composition comprises between
0.5 and 1 wt. % of scrambled-form linaclotide
[0082] In some embodiments, the composition comprises a total
degradant concentration of less than about 10 wt. %. In some
embodiments, the composition comprises a total degradant
concentration of less than about 8 wt. %. In some embodiments, the
composition comprises a total degradant concentration of less than
about 7 wt. %. In some embodiments, the composition comprises a
total degradant concentration of less than about 6.5 wt. %. In some
embodiments, the composition comprises a total degradant
concentration of less than about 6 wt. %. In some embodiments, the
composition comprises a total degradant concentration of less than
about 5.5 wt. %. In some embodiments, the composition comprises a
total degradant concentration of less than about 5 wt. %. In some
embodiments, the composition comprises a total degradant
concentration of less than about 4 wt. %. In some embodiments, the
composition comprises a total degradant concentration of less than
about 3 wt. %. In some embodiments, the composition comprises a
total degradant concentration of less than about 2.5 wt. %. In some
embodiments, the composition comprises a total degradant
concentration of less than about 2 wt. %. In some embodiments, the
composition comprises a total degradant concentration of less than
about 1 wt. %.
[0083] The pharmaceutical composition can be used to treat and
diseases, disorders and conditions that are responsive to treatment
with agonists of the GC-C receptor. For example, the composition
can be used to treat gastrointestinal disorders including, but not
limited to, irritable bowel syndrome, constipation-predominant
irritable bowel syndrome, dyspepsia (including functional dyspepsia
or non-ulcer dyspepsia), gastrointestinal motility disorders,
functional gastrointestinal disorders, gastroesophageal reflux
disease (GERD), Crohn's disease, ulcerative colitis, inflammatory
bowel disease, functional heartburn, gastroparesis, chronic
intestinal pseudo-obstruction (or colonic pseudo-obstruction), and
disorders and conditions associated with constipation, for example,
chronic constipation, opioid induced constipation, post-surgical
constipation (post-operative ileus), constipation associated with
neuropathic disorders or a combination of symptoms thereof (such as
a combination of irritable bowel syndrome and chronic
constipation), or inflammation or pain associated therewith. In
some embodiments, a method is provided for treating
gastrointestinal disorders in a patient (e.g., mammal or human)
diagnosed with one or more gastrointestinal disorders or
conditions, wherein the method comprises administering an effective
amount of the composition to the patient.
[0084] In another embodiment, a method is provided for increasing
intestinal motility in a patient in need thereof, comprising
administering an effective amount of the composition to the
patient. Intestinal motility involves spontaneous coordinated
dissentions and contractions of the stomach, intestines, colon and
rectum to move food through the gastrointestinal tract during the
digestive process.
[0085] In some embodiments, the methods may comprise administering
a therapeutically effective amount of the pharmaceutical
composition to a patient in need thereof.
[0086] An effective amount of a composition comprising linaclotide
or a pharmaceutically acceptable salt thereof required to achieve
desired results (such as desired treatment and/or symptom relief)
of a subject is dependent on several understood factors, such as
the identity and severity of the disorder being treated, as well as
the age, weight, etc., of the patient being treated.
[0087] A subject or patient in whom administration of the
pharmaceutical composition is an effective therapeutic regimen for
a disease or disorder is preferably a human, but can be any animal,
including a laboratory animal in the context of a clinical trial or
screening or activity experiment. Thus, as can be readily
appreciated by one of ordinary skill in the art, the methods,
compounds and compositions described herein are particularly suited
for administration to any animal, particularly a mammal, and
including, but by no means limited to, humans, rodents and
non-rodents, such as feline or canine subjects, farm animals, such
as but not limited to bovine, equine, caprine, ovine, and porcine
subjects, wild animals (whether in the wild or in a zoological
garden), research animals, such as mice, rats, rabbits, goats,
sheep, pigs, dogs, cats, etc., avian species, such as chickens,
turkeys, songbirds, etc., e.g., for veterinary medical use.
[0088] In some embodiments, the effective dose range of linaclotide
for adult humans is from 25 .mu.g to 6 mg per day orally. In some
embodiments, the dose range is 25 .mu.g to 2 mg per day orally. In
some embodiments, the dose range for adult humans is 50 .mu.g to 1
mg per day orally (e.g., 50 .mu.g, 100 .mu.g, 150 .mu.g, 200 .mu.g,
250 .mu.g, 300 .mu.g, 350 .mu.g, 400 .mu.g, 450 .mu.g, 500 .mu.g,
550 .mu.g, 600 .mu.g, 650 .mu.g, 700 .mu.g, 750 .mu.g, 800 .mu.g,
850 .mu.g, 900 .mu.g, 950 .mu.g or 1 mg). In some embodiments, the
dose range is 100 .mu.g to 600 .mu.g per day orally. In some
embodiments, the dose is 50 .mu.g, 100 .mu.g, 150 .mu.g, 200 .mu.g,
300 .mu.g, 400 .mu.g, 500 .mu.g or 600 .mu.g linaclotide per day
orally. In some embodiments, the dose is 50 .mu.g linaclotide per
day orally. In some embodiments, the dose is 100 .mu.g linaclotide
per day orally. In some embodiments, the dose is 150 .mu.g
linaclotide per day orally. In some embodiments, the dose is 200
.mu.g linaclotide per day orally. In some embodiments, the dose is
300 .mu.g linaclotide per day orally. In some embodiments, the dose
is 400 .mu.g linaclotide per day orally. In some embodiments, the
dose is 500 .mu.g linaclotide per day orally. In some embodiments,
the dose is 600 linaclotide per day orally.
[0089] In some embodiments, the effective pediatric dose range of
linaclotide is from 0.05 .mu.g to 2 mg per day orally. In some
embodiments, the effective pediatric dose range of linaclotide is
from 0.05 .mu.g to 100 .mu.g per day orally. In some embodiments,
the effective pediatric dose range of linaclotide is from 0.1 .mu.g
to 90 .mu.g per day orally. In some embodiments, the effective
pediatric dose range of linaclotide is from 0.1 .mu.g to 50 .mu.g
per day orally. In some embodiments, the effective pediatric dose
range of linaclotide is from 0.1 .mu.g to 25 .mu.g per day orally.
In some embodiments, the effective pediatric dose range of
linaclotide is from 0.1 .mu.g to 10 .mu.g per day orally. In some
embodiments, the effective pediatric dose range of linaclotide is
from 0.1 .mu.g to 5 .mu.g per day orally. In some embodiments, the
effective pediatric dose range of linaclotide is from 0.1 .mu.g to
1.mu.g per day orally. In some embodiments, the effective pediatric
dose range of linaclotide is from 0.1 .mu.g to 0.5 .mu.g per day
orally. In some embodiments, the effective pediatric dose range of
linaclotide is 0.1 .mu.g per day orally. In some embodiments, the
effective pediatric dose range of linaclotide is 0.15 .mu.g per day
orally. In some embodiments, the effective pediatric dose range of
linaclotide is 0.25 .mu.g per day orally. In some embodiments, the
effective pediatric dose range of linaclotide is 0.5 .mu.g per day
orally. In some embodiments, the effective pediatric dose range of
linaclotide is 3.5 .mu.g per day orally. In some embodiments, the
effective pediatric dose range of linaclotide is 15 .mu.g per day
orally. In some embodiments, the effective pediatric dose range of
linaclotide is 45 .mu.g per day orally. In some embodiments, the
effective pediatric dose range of linaclotide is 60 .mu.g per day
orally. In some embodiments, the effective pediatric dose range of
linaclotide is 90 .mu.g per day orally.
[0090] In some embodiments, the unit dosage form and daily dose are
equivalent. In some embodiments, the unit dosage form is
administered with food at anytime of the day, without food at
anytime of the day, with food after an overnight fast (e.g., with
breakfast). In some embodiments, the unit dosage form is
administered once a day, twice a day or three times a day. In some
embodiments, one, two or three unit dosage forms will contain the
daily oral dose of linaclotide. The precise amount of compound
administered to a patient will be the responsibility of the
attendant physician. However, the dose employed will depend on a
number of factors, including the age and sex of the patient, the
precise disorder being treated, and its severity.
[0091] In some embodiments, the compositions are administered as a
monotherapy. In some embodiments, the composition consists
essentially of an effective amount of linaclotide. In some
embodiments, the composition consists of an effective amount of
linaclotide.
[0092] In some embodiments, the compositions are directly
administered to a patient, for example, in the form of a capsule,
tablet or orally-disintegrating composition (e.g.,
orally-disintegrating tablet or film). In some embodiments, the
compositions are dissolved, disintegrated and/or mixed on or within
food or beverage prior to administration to patients (e.g., elderly
or pediatric patients). In some embodiments, the composition is
dissolved or disintegrated in a liquid, solution, or fluid
optionally containing stabilizing agent(s), preservative(s),
sweetener(s), or the like, etc. prior to administration to a
patient (e.g., elderly or pediatric patient).
[0093] In some embodiments, the composition is a multiple dose
composition, i.e., containing two, three, five, seven, ten,
fifteen, twenty, twenty-five, thirty, forty, fifty, sixty, seventy,
eighty, ninety or more daily doses of linaclotide. In some
embodiments, one or more orally-disintegrating tablets or films
containing 3.5 .mu.g of linaclotide are dissolved or disintegrated
within a liquid, solution or fluid to provide a composition that
contains a five day supply of 0.5 .mu.g of linaclotide dosages of
the composition ("a five dose composition"). In some embodiments,
one or more orally-disintegrating tablets or films containing 15
.mu.g of linaclotide are dissolved or disintegrated within a
liquid, solution, or fluid to provide a composition that contains a
thirty day supply of 0.5 .mu.g of linaclotide dosages of the
composition ("a thirty dose composition"). In some embodiments, one
or more orally-disintegrating tablets or films containing 45 .mu.g
of linaclotide are dissolved or disintegrated within a liquid,
solution, or fluid to provide a composition that contains a ninety
day supply of 0.5 .mu.g of linaclotide dosages of the composition
("a ninety dose composition"). In some embodiments, one or more
orally-disintegrating tablets or films containing 60 .mu.g of
linaclotide are dissolved or disintegrated within a liquid,
solution, or fluid to provide a composition that contains a 120 day
supply of 0.5 .mu.g of linaclotide dosages of the composition ("a
120 dose composition"). In some embodiments, one or more
orally-disintegrating tablets or films containing 90 .mu.g of
linaclotide are dissolved or disintegrated within a liquid,
solution, or fluid to provide a composition that contains a 180 day
supply of 0.5 .mu.g of linaclotide dosages of the composition ("a
180 dose composition").
[0094] In other embodiments, the compositions are administered as
part of a combination therapy. For example, a composition may be
used in combination with other drugs or therapies that are used in
the treatment, prevention, suppression, and/or amelioration of the
diseases or conditions for which compounds of the invention are
useful. The linaclotide can be co-administered or co-formulated
with other medications. In one embodiment, the linaclotide
composition can be co-administered with other medications used to
treat gastrointestinal disorders including but not limited to acid
suppressing agents such as Histamine-2 receptor agonists (H2As)
and/or proton pump inhibitors (PPIs).
[0095] Such other drug(s) may be administered, by a route and in an
amount commonly used therefore, contemporaneously or sequentially
with a compound of the invention. When a compound of the present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical unit dosage form containing such other drugs in
addition to the compound of the invention may be employed.
Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active
components, in addition to a compound of invention.
[0096] Several methods can be used for evaluating the bioactivity
of the linaclotide composition, including, but not limited to,
immunoassays (e.g., enzyme-linked immunosorbent assay), radioimmuno
assays, immunoradiometric assays, gel electrophoresis (e.g.,
SDS-PAGE), high performance liquid chromatography (HPLC), and/or
high performance capillary electrophoresis (HPCE). In some
embodiments, the bioactivity of the composition is assessed by a
method comprising fixing linaclotide, incubating linaclotide with
guanylate cyclase C (GCC), incubating GCC bound linaclotide with
antibodies against GCC, incubating GCC antibody-bound linaclotide
with fluorescently labeled antibodies against GCC antibodies, and
detecting the linaclotide bound to the GCC antibodies by measuring
the fluorescence intensity using a plate reader. The drug
concentration can then be calculated based on the fluorescence
reading of the solution.
[0097] For example, the bioactivity of the linaclotide compositions
can be assessed and quantified using the following method, although
other methods are available. The composition is added to a
volumetric flask containing 60 ml of phosphate buffer having a pH
of 4.5, and the flask is shaken for 60 minutes. 0.2 ml of the
supernatant is then removed, and is added into one or more wells of
a 96-well plate that is coated with GCC. The plate is sealed and
incubated at 37.degree. C. for 2 hr. At the end of incubation, the
sample is removed and the plate is washed with phosphate buffered
saline (PBS). The bound linaclotide is then incubated for 1 hour,
at room temperature, with GCC (such as is available from
Sigma-Aldrich Inc.) labeled with fluorescein isocyanate (FITC) in
blocking buffer. After incubation, the well is washed with PBS. The
fluorescence intensity of the end product is detected, for example,
by using a plate reader. The linaclotide concentration is then
calculated based on the fluorescence reading of the solution.
Definitions
[0098] Linaclotide is a peptide that consists of the amino acid
sequence Cys.sub.1 Cys.sub.2 Glu.sub.3 Tyr.sub.4 Cys.sub.5
Cys.sub.6 Asn.sub.7 Pros Ala.sub.9 Cys.sub.10 Thr.sub.11 Gly.sub.12
Cys.sub.13 Tyr.sub.14. Linaclotide can exist in free form or in the
form of a pharmaceutically acceptable salt or hydrate.
[0099] As used herein, unless otherwise indicated, the term "entry
into a use environment" means contact of the composition with
saliva of the patient to whom it is administered, or with a fluid
intended to simulate saliva, e.g., having a pH greater than 5, or
with a phosphate buffer solution having a pH of 4.5 and maintained
at 37.+-.1.degree. C.
[0100] The term "released from", when referring to the release of
linaclotide from the composition, unless otherwise indicated, is
used herein to mean that the linaclotide no longer remains in a
composition form.
[0101] As used herein, unless otherwise indicated, "stabilizing
agent" refers to a polymer, sterically hindered primary amine
(e.g., amino acid), or cation (e.g., metal cation) component of the
composition which is included in the composition in a stabilizing
amount. For example, a polymeric stabilizing agent is a polymer
that is included in the composition in a stabilizing amount.
Similarly, a sterically hindered primary amine stabilizing agent is
a sterically hindered primary amine that is included in the
composition in a stabilizing amount. Moreover, a cationic
stabilizing agent is a cation that is included in the composition
in a stabilizing amount.
[0102] As used herein, unless otherwise indicated, "stabilizing
amount" refers to a concentration, within the composition, of a
polymer, sterically hindered primary amine (e.g., amino acid), or
metal cation component at which the component increases the
stability of linaclotide in the composition, as compared to a
similar composition not having a stabilizing amount of the same
component.
[0103] As used herein, unless otherwise indicated, a "low-dose
pharmaceutical composition" is a pharmaceutical composition that
comprises less than 125 .mu.g of linaclotide, for example less than
110 .mu.g, less than 100 .mu.g, less than 80 .mu.g, less than 70
.mu.g, less than 60 .mu.g, or even less than 50 .mu.g of
linaclotide (for example, between 0.001 .mu.g and 125 .mu.g,
between 0.001 .mu.g and 100 .mu.g, between 0.001 .mu.g and 80
.mu.g, or between 0.001 .mu.g and 50 .mu.g of linaclotide).
[0104] As used herein, unless otherwise indicated, the term
"substantially all" means at least about 90%, for example, at least
about 95% or even at least about 99%.
[0105] As used herein, unless otherwise indicated, the term
"isolated and purified" means at least 95 percent pure (for
example, at least 96% pure, at least 97% pure, at least 98% pure,
or even at least 99% pure), as measured, for example, by
chromatographic purity using HPLC.
[0106] As used herein, unless otherwise indicated, "therapeutically
effective amount" means the amount of a linaclotide or a
pharmaceutically acceptable salt thereof that, when administered to
a mammal for treating a state, disorder or condition, is sufficient
to effect a treatment (as defined below). The "therapeutically
effective amount" will vary depending on the compound, the disease
and its severity and the age, sex, weight, physical condition and
responsiveness of the mammal to be treated. For example, a
therapeutically effective amount of linaclotide, or its
pharmaceutically acceptable salt or hydrate, can be an amount
effective to treat gastrointestinal disorders, including irritable
bowel syndrome, constipation-predominant irritable bowel syndrome,
chronic constipation, opioid induced constipation and/or
dyspepsia.
[0107] As used herein, unless other indicated, "pharmaceutically
acceptable" means biologically or pharmacologically compatible for
in vivo use in animals or humans, and preferably means, approved by
a regulatory agency of the Federal or a state government or listed
in the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans.
[0108] As used herein, unless otherwise indicated, the term
"treat", in all its verb forms, is used herein to mean to relieve,
alleviate, prevent, and/or manage at least one symptom of a
disorder in a subject, the disorder including, for example, a
gastrointestinal disorder, such as, irritable bowel syndrome,
constipation-predominant irritable bowel syndrome, chronic
constipation, opioid induced constipation, dyspepsia, or a
combination of symptoms thereof. Within the meaning of the present
invention, the term "treat" also denotes, to arrest, delay the
onset (i.e., the period prior to clinical manifestation of a
disease) and/or reduce the risk of developing or worsening a
disease. The term "treatment" means the act of "treating" as
defined above.
[0109] As used herein, unless otherwise indicated, the term
"additives" refers to a pharmaceutically acceptable additive.
Pharmaceutically acceptable additives include, without limitation,
binders, disintegrants, dispersing additives, lubricants, glidants,
antioxidants, coating additives, diluents, surfactants, flavoring
additives, humectants, absorption promoting additives, controlled
release additives, anti-caking additives, anti-microbial agents
(e.g., preservatives), colorants, desiccants, plasticizers and
dyes.
[0110] As used herein, unless otherwise indicated, an "excipient"
is any pharmaceutically acceptable additive, filler, binder or
agent.
[0111] As used herein, unless otherwise indication, "stressed
conditions" refer to 40.degree. C. and 75% relative humidity
(RH).
[0112] As used here, unless otherwise indicated, the terms "about"
and "approximately" mean within an acceptable error range for the
particular value as determined by one of ordinary skill in the art,
which will depend, in part, on how the value is measured or
determined, i.e., the limitations of the measurement system. For
example, "about" can mean within 1 or more than 1 standard
deviation, per practice in the art. Alternatively, "about" with
respect to the compositions can mean plus or minus a range of up to
20%, preferably up to 10%. Alternatively, particularly with respect
to biological systems or processes, the term can mean within an
order of magnitude, preferably within 5-fold, and more preferably
within 2-fold, of a value. Particular values are described in the
application and claims, unless otherwise stated the term "about"
means within an acceptable error range for the particular
value.
[0113] All weight percentages (i.e., "% by weight" and "wt. %" and
w/w) referenced herein, unless otherwise indicated, are measured
relative to the total weight of the pharmaceutical composition.
[0114] The term "consisting essentially of", and variants thereof,
when used to refer to the composition, are used herein to mean that
the composition includes linaclotide and other desired
pharmaceutically inactive additives, excipients, and/or components
(e.g., polymers, sterically hindered primary amines, cations,
filling agents, binders, carriers, excipients, diluents,
disintegrating additives, lubricants, solvents, dispersants,
coating additives, absorption promoting additives, hydrolysis
products, formaldehyde imine products, oxidation products,
acetylation products, deamidation products, multimers, controlled
release additives, anti-caking additives, anti-microbial additives,
preservatives, sweetening additives, colorants, flavors,
desiccants, plasticizers, dyes, or the like), and no other active
pharmaceutical ingredient(s).
EXAMPLES
[0115] The following examples are merely illustrative of the
present invention and should not be construed as limiting the scope
of the invention in any way as many variations and equivalents that
are encompassed by the present invention will become apparent to
those skilled in the art upon reading the present disclosure.
[0116] The following tests were employed in the examples section,
unless otherwise indicated:
[0117] 1) Stability of linaclotide compositions. For stability
evaluation, linaclotide compositions (0.15 mg theoretical, actual
0.135 mg) were packaged into a HDPE bottle with desiccant, and
stored under at 40.degree. C. and 75% RH ("stressed conditions").
The amount of linaclotide was assayed initially and after up to 18
months of storage at stressed conditions. The concentration of
linaclotide was analyzed and quantified using an HPLC method with
the following mobile phase gradient: Mobile phase A: 50 mM of
sodium perchlorate in a solvent containing 76% water and 24%
acetonitrile and 0.1% of trifluoroacetic acid; Mobile phase B: 50
mM of sodium perchlorate in a solvent containing 5% water and 95%
acetonitrile and 0.1% of trifluoroacetic acid; Flow rate: 0.6
ml/min; Column: YMC Pro C18, 150 mm.times.3 mm ID, 3 .mu.m or
equivalent; Column temperature: 40.degree. C.; Fluorescence
detection: excitation: 274 nm; emission: 303 nm; Injection volume:
100 .mu.l.
[0118] 2) Analysis of total degradants in the pharmaceutical
composition: Degradant analysis was performed using an HPLC method
employing the following conditions: Mobile phase A:
Water:acetonitrile 98:2, with 0.1% (v/v) of trifluoroacetic acid;
Mobile phase B: Water:acetonitrile 595, with 0.1% (v/v) of
trifluoroacetic acid; Flow rate : 0.6 ml/min; Column: YMC Pro C18,
150 mm.times.3 mm ID, 3 .mu.m or equivalent; Column temperature:
40.degree. C.; UV detection: excitation: 220 nm; Injection volume:
50 .mu.l. The percentage amounts of degradants in the composition
were calculated by quantifying the area of all peaks in the HPLC
chromatogram to obtain the "total peak area", and dividing the peak
area of each degradant by the total peak area. Specific degradants
assayed include, for example, the hydrolysis product, Asp-7.
Example 1
[0119] Linaclotide beads were prepared in the following manner
using the components set forth in Table 1. First, a linaclotide
solution was prepared by combining linaclotide, polyvinyl alcohol,
calcium chloride, meglumine and water in the concentrations set
forth in Table 1. The linaclotide solution was then pH-adjusted to
about 2.5 and mixed until clear. Next, the linaclotide solution was
layered onto isomalt beads by spraying the beads with the
linaclotide solution using a Wurster process. The
linaclotide-layered beads were then dried until the product loss on
drying (LOD) was less than about 3%.
TABLE-US-00001 TABLE 1 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1915 95.8 Meglumine
2.6 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. QS
Purified water* 1000 QS TOTAL 2000 100.0 *Water is removed during
the manufacturing process
[0120] The stability performance of the linaclotide beads were
assessed following storage of the beads for 1 month at 40.degree.
C. and 75% RH in 45 cc HDPE bottles (induction sealed and not
containing desiccant). Results of the stability performance assay
are set forth in Table 2.
TABLE-US-00002 TABLE 2 Results of stability performance assay Asp-7
Imine Time Degradant Degradant Purity % initial 0.11 <0.1 97.8 1
wk 0.25 0.11 96.5 2 wk 0.31 <0.1 96.5 1 m 0.37 <0.1 92.6
Example 2
[0121] Linaclotide beads were prepared in the following manner
using the components set forth in Table 3. First, a linaclotide
solution was prepared by combining linaclotide, polyvinyl alcohol,
calcium chloride, histidine and water in the concentrations set
forth in Table 3. The linaclotide solution was then pH-adjusted to
about 2.5 and mixed until clear. Next, the linaclotide solution was
layered onto isomalt beads by spraying the beads with the
linaclotide solution using a Wurster process. The
linaclotide-layered beads were then dried until the product loss on
drying (LOD) was less than about 3%.
TABLE-US-00003 TABLE 3 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Histidine
2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 3
[0122] Linaclotide beads were prepared in the manner described in
Example 2 using the components set forth in Table 4.
TABLE-US-00004 TABLE 4 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Leucine 2
0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 4
[0123] Linaclotide beads were prepared in the manner described in
Example 2 using the components set forth in Table 5.
TABLE-US-00005 TABLE 5 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Arginine
2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 5
[0124] Linaclotide beads were prepared in the manner described in
Example 2 using the components set forth in Table 6.
TABLE-US-00006 TABLE 6 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Lysine 2
0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 6
[0125] The stability and dissolution performance were assessed for
the linaclotide beads prepared in Examples 2-5 following storage of
the beads at 40.degree. C. and 75% RH in HDPE bottles (sealed with
heat and not containing desiccant). Results of the stability and
dissolution performance assays are set forth in Tables 7-8 and FIG.
1 (which illustrates imine degradant concentrations).
TABLE-US-00007 TABLE 7 Stability of linaclotide beads at 40.degree.
C., 75% RH Assay (normalized) Amino acid 1 wk 2 wk 1 mo Histidine
96.5 99.7 93.1 Leucine 95.9 95.2 93.5 Lysine 92.5 91.4 87.6
Arginine 96.9 92.5 89.5
TABLE-US-00008 TABLE 8 Degradation profile of linaclotide beads at
40.degree. C., 75% RH Duration of Asp-7 Imine Amino acid Storage
Degradant Degradant Purity Histidine initial 0.18 0.16 98.3 1 wk
0.11 0.27 98.3 2 wk 0.15 0.41 96.5 1 m 0.26 0.61 93.4 Leucine
initial -- 0.18 97.6 1 wk 0.17 0.79 96.9 2 wk 0.19 1.00 94.8 1 m
0.20 1.92 90.7 Lysine initial 0.17 0.24 97.5 1 wk 0.12 1.74 94.8 2
wk 0.18 2.57 92.0 1 m 0.14 3.64 85.9 Arginine initial 0.10 0.14
98.9 1 wk 0.18 1.41 95.7 2 wk 0.28 2.12 92.8 1 m 0.24 2.55 88.6
Example 7
[0126] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 9.
TABLE-US-00009 TABLE 9 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Melamine
2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 8
[0127] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 10.
TABLE-US-00010 TABLE 10 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Gelatin 2
0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 9
[0128] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 11.
TABLE-US-00011 TABLE 11 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Glycine 2
0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 10
[0129] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 12.
TABLE-US-00012 TABLE 12 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8
Glycine-Leucine 2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4
HCl Q.S. -- Purified water* 1000 -- TOTAL 2000 100.0 *Water is
removed during the manufacturing process
Example 11
[0130] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 13.
TABLE-US-00013 TABLE 13 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8
Leucine-Glycine 2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4
HCl Q.S. -- Purified water* 1000 -- TOTAL 2000 100.0 *Water is
removed during the manufacturing process
Example 12
[0131] Linaclotide beads may be prepared in the manner described in
Example 2 using the components set forth in Table 14.
TABLE-US-00014 TABLE 14 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8 Albumin 2
0.1 Calcium chloride dehydrate 2.0 0.1 PVA 80 4 HCl Q.S. --
Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed during
the manufacturing process
Example 13
[0132] Linaclotide beads were prepared in the manner described in
Example 2 using the components set forth in Table 15.
TABLE-US-00015 TABLE 15 Linaclotide beads, 5 .mu.g/50 mg Components
Weight (g) Wt. % Linaclotide 0.24 0.012 Isomalt 1916 95.8
Asparagine 2 0.1 Calcium chloride dihydrate 2.0 0.1 PVA 80 4 HCl
Q.S. -- Purified water* 1000 -- TOTAL 2000 100.0 *Water is removed
during the manufacturing process
[0133] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims. It is further to be understood that all values are
approximate, and are provided for description.
[0134] All patents, patent applications, publications, product
descriptions, and protocols are cited throughout this application,
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
* * * * *