U.S. patent application number 12/990097 was filed with the patent office on 2011-02-24 for methods and compositions for oral administration of exenatide.
This patent application is currently assigned to ORAMED LTD.. Invention is credited to Miriam Kidron.
Application Number | 20110046053 12/990097 |
Document ID | / |
Family ID | 41265104 |
Filed Date | 2011-02-24 |
United States Patent
Application |
20110046053 |
Kind Code |
A1 |
Kidron; Miriam |
February 24, 2011 |
METHODS AND COMPOSITIONS FOR ORAL ADMINISTRATION OF EXENATIDE
Abstract
This invention provides compositions comprising a byetta, fish
oil, and a protease inhibitor, method for treating diabetes
mellitus, comprising administering same, and methods for oral or
rectal administration of a byetta.
Inventors: |
Kidron; Miriam; (Jerusalem,
IL) |
Correspondence
Address: |
WOLF GREENFIELD & SACKS, P.C.
600 ATLANTIC AVENUE
BOSTON
MA
02210-2206
US
|
Assignee: |
ORAMED LTD.
Jerusalem
IL
|
Family ID: |
41265104 |
Appl. No.: |
12/990097 |
Filed: |
May 3, 2009 |
PCT Filed: |
May 3, 2009 |
PCT NO: |
PCT/IL2009/000461 |
371 Date: |
October 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61071538 |
May 5, 2008 |
|
|
|
Current U.S.
Class: |
514/6.7 |
Current CPC
Class: |
A61K 31/202 20130101;
A61P 5/48 20180101; A61P 43/00 20180101; A61K 9/0031 20130101; A61P
3/10 20180101; A61K 9/2846 20130101; A61K 9/0053 20130101; A61K
31/202 20130101; A61K 38/56 20130101; A61P 3/04 20180101; A61P 5/50
20180101; A61P 19/02 20180101; A61P 9/12 20180101; A61K 38/26
20130101; A61P 1/00 20180101; A61K 9/4866 20130101; A61K 31/22
20130101; A61K 38/57 20130101; A61K 2300/00 20130101; A61P 9/10
20180101; A61K 38/26 20130101; A61K 38/57 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/6.7 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61P 3/10 20060101 A61P003/10 |
Claims
1-71. (canceled)
72. A composition comprising an exenatide, a protease inhibitor,
and an omega-3 fatty acid, wherein said composition is an oral
pharmaceutical composition.
73. The composition of claim 72, wherein said omega-3 fatty acid is
derived from fish oil.
74. The composition of claim 72, wherein said inhibitor is soybean
trypsin inhibitor (SBTI).
75. The composition of claim 72, wherein said protease is a serine
protease.
76. The composition of claim 72, wherein said protease is
trypsin.
77. The composition of claim 72, further comprising a substance
that enhances absorption of said exenatide through an intestinal
mucosal barrier.
78. The composition of claim 77, wherein said substance is EDTA or
a salt thereof.
79. The composition of claim 77, wherein said substance is a bile
acid or alkali metal salt thereof.
80. The composition of claim 72, further comprising a coating that
inhibits digestion of said exenatide in a stomach of a subject.
81. The composition of claim 80, wherein said coating is an enteric
coating or gelatin coating.
82. A method for oral administration of exenatide to a subject,
whereby a substantial fraction of said exenatide retains its
activity after absorption through an intestinal mucosal barrier of
said subject, comprising administering orally to said subject a
pharmaceutical composition comprising said exenatide, a protease
inhibitor, and an omega-3 fatty acid.
83. The method of claim 82, wherein said omega-3 fatty acid is
derived from fish oil.
84. The method of claim 82, wherein said protease is trypsin.
85. The method of claim 82, wherein said pharmaceutical composition
further comprises EDTA or a salt thereof.
86. The method of claim 82, wherein said pharmaceutical composition
further comprises an enteric coating or gelatin coating.
87. The method of claim 82, whereby food intake in said subject is
reduced.
88. A method for treating diabetes mellitus in a subject,
comprising administering orally to said subject a pharmaceutical
composition comprising exenatide, a protease inhibitor, and an
omega-3 fatty acid, thereby treating diabetes mellitus.
89. The method of claim 88, wherein said omega-3 fatty acid is
derived from fish oil.
90. The method of claim 88, wherein said protease is trypsin.
91. The method of claim 88, wherein said pharmaceutical composition
further comprises EDTA or a salt thereof.
92. The method of claim 88, wherein said pharmaceutical composition
further comprises an enteric coating or gelatin coating.
Description
FIELD OF INVENTION
[0001] This invention provides oral compositions comprising
Exenatide, and a method for administering same.
BACKGROUND OF THE INVENTION
[0002] Due to improved biotechnology, the accessibility of
biologically active peptides to the pharmaceutical industry has
increased considerably. However, a limiting factor in the
development of peptide drugs is the relative ineffectiveness when
given perorally. Almost all peptide drugs are parenterally
administered, although parenterally administered peptide drugs are
often connected with low patient compliance.
[0003] Exenatide is a glucagon-like peptide (GLP-1) agonist that
was approved by the Food and Drug Administration for adjunctive
therapy when patients with type 2 diabetes have not been optimally
controlled on metformin. It is an incretin mimetic and potentiates
exenatide secretion while inhibiting glucagon secretion and slowing
gastric emptying.
[0004] Exenatide (marketed as Byetta) is manufactured and marketed
by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide is a
synthetic version of exendin-4, a hormone in the saliva of the Gila
monster, a lizard native to several Southwestern American states.
Typical human responses to exenatide include improvements in the
initial rapid release of endogenous insulin, suppression of
pancreatic glucagon release, delayed gastric emptying, and reduced
appetite--all of which function to lower blood glucose. Unlike
sulfonylureas and meglitinides, exenatide increases insulin
synthesis and secretion in the presence of glucose only, lessening
the risk of hypoglycemia. Byetta is also being used by some
physicians to treat insulin resistance.
[0005] Exenatide augments pancreas response (i.e. increases insulin
secretion) in response to eating meals; the result is the release
of a higher, more appropriate amount of insulin that helps lower
the rise in blood sugar from eating. Once blood sugar levels
decrease closer to normal values, the pancreas response to produce
insulin is reduced; however, other drugs (like injectable insulin)
are effective at lowering blood sugar, but can "overshoot" their
target and cause blood sugar to become too low, resulting in the
dangerous condition of hypoglycemia.
[0006] Exenatide also suppresses pancreatic release of glucagon in
response to eating, which helps stop the liver from overproducing
sugar when it is unneeded, which prevents hyperglycemia (high blood
sugar levels).
[0007] Exenatide helps slow down gastric emptying and thus
decreases the rate at which meal-derived glucose appears in the
bloodstream.
[0008] Exenatide has a subtle yet prolonged effect to reduce
appetite and thus may prevent weight gain. Most people using
Exenatide slowly lose weight, and generally the greatest weight
loss is achieved by people who are the most overweight at the
beginning of exenatide therapy. Clinical trials have demonstrated
that the weight reducing effect continues at the same rate through
2.25 years of continued use. When separated into weight loss
quartiles, the highest 25% experience substantial weight loss and
the lowest 25% experience no loss or small weight gain.
[0009] Exenatide reduces liver fat content. Fat accumulation in the
liver or non-alcoholic fatty liver disease (NAFLD) is strongly
related with several metabolic disorders, in particular low HDL
cholesterol and high triglycerides, present in patients with type 2
diabetes. It became apparent that exenatide reduced liver fat in
mice and more recently in man.
[0010] Exenatide is a polypeptide consisting of 39 amino acids with
a molecular weight of 4186.6. Ex vivo human placental perfusion
studies detected minimal levels on the fetal side (fetal: maternal
ratio 0.017).
[0011] Exenatide is currently administered as a subcutaneous
injection, generally concomitantly with a sulfonylurea or
metformin. Although it has a modest effect on lowering fasting
glucose levels, it markedly reduces postprandial glucose.
[0012] The present invention addresses the need for an alternate
solution for administration of exenatide.
SUMMARY OF THE INVENTION
[0013] This invention provides, in one embodiment, a composition
comprising an exenatide and a protease inhibitor, wherein the
composition is an oral pharmaceutical composition or a rectal
pharmaceutical composition.
[0014] In another embodiment, the present invention provides a
method for oral or rectal administration of exenatide to a subject,
whereby a substantial fraction of exenatide retains its activity
after absorption, through an intestinal mucosal barrier or through
a rectal tissue of said subject, comprising administering orally or
rectally to a subject a pharmaceutical composition comprising said
exenatide.
[0015] In another embodiment, the present invention provides a
method for treating diabetes mellitus in a subject, comprising
administering orally or rectally to a subject a pharmaceutical
composition comprising exenatide, thereby treating diabetes
mellitus.
[0016] In another embodiment, the present invention provides a
method for reducing food intake in a subject, comprising
administering orally or rectally to a subject a pharmaceutical
composition comprising exenatide, thereby reducing food intake in a
subject.
[0017] In another embodiment, the present invention provides a
method for reducing gastric motility in a subject, comprising
administering orally or rectally to a subject a pharmaceutical
composition comprising exenatide, thereby reducing gastric motility
in a subject.
[0018] In another embodiment, the present invention provides a
method for lowering plasma glucagon in a subject, comprising
administering orally or rectally to said subject a pharmaceutical
composition comprising exenatide, thereby lowering plasma glucagon
in a subject.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1. Is a graph showing the blood glucose lowering effect
of an Exendin-4-oral dosage form compared to control in dogs.
[0020] FIG. 2. Is a graph comparing the blood glucose lowering
effect of an Exendin-4 in a rectal dosage form (hard gelatin
capsule, 100 .mu.g Excedrin-4), injectable dosage forms (2.5 .mu.g
Byetta GeneScript and 2.5 .mu.g Byetta Commercial), and control in
dogs, the values are calculated as .DELTA. time 0 (the
concentration of blood glucose at time 0 was deducted from each
value obtained at a given time).
[0021] FIG. 3. Is a graph comparing the blood glucose lowering
effect of an Exendin-4 in an oral dosage form (100 .mu.g
Excedrin-4), control, and injectable dosage forms (2.5 .mu.g Byetta
GeneScript and 2.5 .mu.g Byetta Commercial) in dogs (the
concentration of blood glucose at time 0 was deducted from each
value obtained at a given time).
DETAILED DESCRIPTION OF THE INVENTION
[0022] This invention provides compositions and methods comprising
exenatide and an omega-3 fatty acid. In another embodiment, the
present invention provides compositions and methods comprising
exenatide and a protease inhibitor. In another embodiment, the
present invention provides compositions and methods comprising
exenatide and an enhancer such as EDTA and salts thereof such as
Na-EDTA. In another embodiment, the present invention provides
compositions and methods comprising exenatide and Na-EDTA. In
another embodiment, the present invention provides compositions and
methods comprising exenatide, omega-3 fatty acid, and Na-EDTA. In
another embodiment, the present invention provides oral
compositions comprising exenatide. In another embodiment, the
present invention provides oral compositions comprising exenatide
and Na-EDTA. In another embodiment, the present invention provides
oral compositions comprising exenatide, omega-3 fatty acid, and
Na-EDTA. In another embodiment, the present invention provides
rectal compositions comprising exenatide and Na-EDTA. In another
embodiment, the present invention provides rectal compositions
comprising exenatide, omega-3 fatty acid, and Na-EDTA. In one
embodiment, the present invention provides a composition comprising
exenatide and an omega-3 fatty acid. As provided herein (Examples),
such compositions have utility in the oral administration of
exenatide, whereby the exenatide is absorbed by the intestines into
the bloodstream in an active form.
[0023] In another embodiment, byetta is the proprietary name for
the active ingredient exenatide. In another embodiment, exenatide
is designated AC2993 and is a synthetic exendin-4. In another
embodiment, exenatide is a 39--amino acid peptide. In another
embodiment, exenatide comprises the amino acid sequence:
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 1). In another
embodiment, exenatide containing the amino acid sequence of SEQ ID
NO: 1. In another embodiment, exenatide comprises an amino acid
sequence having at least 70% identity to SEQ ID NO: 1. In another
embodiment, exenatide comprises an amino acid sequence having at
least 80% identity to SEQ ID NO: 1. In another embodiment,
exenatide comprises an amino acid sequence having at least 90%
identity to SEQ ID NO: 1. In another embodiment, exenatide
comprises an amino acid sequence having at least 95% identity to
SEQ ID NO: 1. In another embodiment, exenatide comprises an amino
acid sequence having at least 99% identity to SEQ ID NO: 1.
[0024] In another embodiment, exenatide oral or rectal formulation
of the invention is effective for diabetic therapy. In another
embodiment, exenatide oral or rectal formulation of the invention
enhances insulin secretion. In another embodiment, exenatide
enhances glucose-dependent insulin secretion. In another
embodiment, exenatide oral or rectal formulation of the invention
suppresses high glucagon secretion. In another embodiment,
exenatide oral or rectal formulation of the invention slows of
gastric-emptying rate. In another embodiment, exenatide oral or
rectal formulation of the invention binds to the pancreatic
glucagon-like peptide-1 (GLP-1) receptor. In another embodiment,
exenatide oral or rectal formulation of the invention reduces food
intake. In another embodiment, exenatide oral or rectal formulation
of the invention causes weight loss. In another embodiment,
exenatide oral or rectal formulation of the invention comprises an
insulin-sensitizing effect. In another embodiment, exenatide oral
or rectal formulation of the invention improves glycemic control
among patients with type 2 diabetes. In another embodiment,
exenatide oral or rectal formulation of the invention improves
glycemic control among patients with type 2 diabetes treated with
sulfonylureas or metformin, alone or in combination.
[0025] In another embodiment, exenatide is Exendin-4 comprising 53%
amino acid sequence overlap with mammalian GLP-1. In another
embodiment, oral or rectal formulation comprising exenatide is
resistant to DPP-IV degradation. In another embodiment, oral or
rectal formulation comprising exenatide reduces postprandial
glycemia. In another embodiment, oral or rectal formulation
comprising exenatide induces the release of insulin and Amylin. In
another embodiment, oral or rectal formulation comprising exenatide
is not associated with weight gain. In another embodiment, oral or
rectal formulation comprising exenatide reduces postprandial serum
triglyceride concentrations. In another embodiment, oral or rectal
formulation comprising exenatide cause less adverse events than an
injectable formulation comprising exenatide. In another embodiment,
treatment with oral or rectal formulation comprising exenatide does
not cause nausea. In another embodiment, treatment with oral or
rectal formulation comprising exenatide cause only mild nausea. In
another embodiment, treatment with oral or rectal formulation
comprising exenatide does not cause gastroparesis.
[0026] In another embodiment, the amount of Exenatide in a
formulation as described herein is 10 mcg to 1 mg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 10 mcg to 25 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 25 mcg to 50 mcg.
In another embodiment, the amount of Exenatide in a formulation as
described herein is 50 mcg to 60 mcg. In another embodiment, the
amount of Exenatide in a formulation as described herein is 60 mcg
to 70 mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 70 mcg to 80 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 80 mcg to 90 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 90 mcg to 100
mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 100 mcg to 110 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 110 mcg to 125 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 125 mcg to 150
mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 150 mcg to 175 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 175 mcg to 200 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 200 mcg to 220
mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 220 mcg to 240 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 240 mcg to 260 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 260 mcg to 300
mcg.
[0027] In another embodiment, the amount of Exenatide in a
formulation as described herein is 300 meg to 350 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 350 mcg to 400 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 400 mcg to 450
mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 450 mcg to 500 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 550 mcg to 600 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 600 mcg to 700
mcg. In another embodiment, the amount of Exenatide in a
formulation as described herein is 700 mcg to 800 mcg. In another
embodiment, the amount of Exenatide in a formulation as described
herein is 800 mcg to 900 mcg. In another embodiment, the amount of
Exenatide in a formulation as described herein is 900 mcg to 1
mg.
[0028] In another embodiment, the Exenatide formulation as
described herein is taken once a day. In another embodiment, the
Exenatide formulation as described herein is taken twice a day. In
another embodiment, the Exenatide formulation as described herein
is taken three times a day. In another embodiment, the Exenatide
formulation as described herein is taken four times a day. In
another embodiment, the Exenatide formulation as described herein
is taken five times a day. In another embodiment, one of skill in
the art determines the dosage of Exenatide formulation as described
herein. In another embodiment, one of skill in the art determines
the daily dose of a Exenatide formulation as described herein. In
another embodiment, one of skill in the art determines the daily
dosing regimen of a Exenatide formulation as described herein.
[0029] In another embodiment, the Exenatide formulation as
described herein is taken at least 15 minutes before a meal. In
another embodiment, the Exenatide formulation as described herein
is taken at least 30 minutes before a meal. In another embodiment,
the Exenatide formulation as described herein is taken at least 45
minutes before a meal. In another embodiment, the Exenatide
formulation as described herein is taken at least 60 minutes before
a meal. In another embodiment, the Exenatide formulation as
described herein is taken at least 75 minutes before a meal. In
another embodiment, the Exenatide formulation as described herein
is taken at least 90 minutes before a meal. In another embodiment,
the Exenatide formulation as described herein is taken at least 100
minutes before a meal. In another embodiment, the Exenatide
formulation as described herein is taken at least 120 minutes
before a meal. In another embodiment, the Exenatide formulation as
described herein is taken at least 150 minutes before a meal. In
another embodiment, the Exenatide formulation as described herein
is taken at least 180 minutes before a meal.
[0030] In another embodiment, the Exenatide formulation as
described herein reduces the side effects associated with an
injectable dosage form comprising Exenatide. In another embodiment,
the Exenatide formulation as described herein reduces nausea as a
side effect which is associated with an injectable dosage form
comprising Exenatide. In another embodiment, the Exenatide
formulation as described herein does not induce nausea as a side
effect which is associated with an injectable dosage form
comprising Exenatide.
[0031] In another embodiment, the use of sustained release dosage
forms (e.g. sustained release micro encapsulation) enables the
treatment frequency to be reduced to once or twice a day. In
another embodiment, the exenatide dosage is increased
correspondingly with decreasing frequency of administration.
[0032] Each amount of exenatide represents a separate embodiment of
the present invention. Methods of measuring exenatide levels are
well known in the art. In another embodiment, levels of C peptide
are measured as well, to determine the relative contributions of
endogenous and exogenous exenatide to observed rises in exenatide
levels. In another embodiment, exenatide levels are measured by any
other method known in the art. Each possibility represents a
separate embodiment of the present invention.
[0033] In some embodiments, omega-3 fatty acid is derived from
vegetable sources such as the seeds of chia, perilla, flax,
walnuts, purslane, lingonberry, seabuckthorn, and hemp. In some
embodiments, omega-3 fatty acids can also be found in the fruit of
the acai palm. In another embodiment, the omega-3 fatty acid has
been provided in the form of a synthetic omega-3 fatty acid. In one
embodiment, the omega-3 fatty acid of methods and compositions of
the present invention has been provided to the composition in the
form of a fish oil. In another embodiment, the omega-3 fatty acid
has been provided in the form of canola oil. In another embodiment,
the omega-3 fatty acid has been provided in the form of flaxseed
oil. In another embodiment, the omega-3 fatty acid has been
provided in the form of any other omega-3 fatty acid-rich source
known in the art. In another embodiment, the omega-3 fatty acid has
been provided in the form of a synthetic omega-3 fatty acid. Each
form of omega-3 fatty acids represents a separate embodiment of the
present invention.
[0034] In another embodiment, the omega-3 fatty acid of methods and
compositions of the present invention is an omega-3 polyunsaturated
fatty acid. In another embodiment, the omega-3 fatty acid is DHA,
an omega-3, polyunsaturated, 22-carbon fatty acid also referred to
as 4, 7, 10, 13, 16, 19-docosahexaenoic acid. In another
embodiment, the omega-3 fatty acid is .alpha.-linolenic acid (9,
12, 15-octadecatrienoic acid). In another embodiment, the omega-3
fatty acid is stearidonic acid (6, 9, 12, 15-octadecatetraenoic
acid). In another embodiment, the omega-3 fatty acid is
eicosatrienoic acid (ETA; 11, 14, 17-eicosatrienoic acid). In
another embodiment, the omega-3 fatty acid is eicosatetraenoic acid
(8, 11, 14, 17-eicosatetraenoic acid). In one embodiment, the
omega-3 fatty acid is eicosapentaenoic acid (EPA; 5, 8, 11, 14,
17-eicosapentaenoic acid): In another embodiment, the omega-3 fatty
acid is eicosahexaenoic acid (also referred to as "EPA"; 5, 7, 9,
11, 14, 17-eicosahexaenoic acid). In another embodiment, the
omega-3 fatty acid is docosapentaenoic acid (DPA; 7, 10, 13, 16,
19-docosapenatenoic acid). In another embodiment, the omega-3 fatty
acid is tetracosahexaenoic acid (6, 9, 12, 15, 18,
21-tetracosahexaenoic acid). In another embodiment, the omega-3
fatty acid is any other omega-3 fatty acid known in the art. Each
omega-3 fatty acid represents a separate embodiment of the present
invention.
[0035] In another embodiment, compositions of the present invention
further comprise a protease inhibitor. In another embodiment,
compositions of the present invention further comprise a
combination of at least two protease inhibitors. As provided
herein, protease inhibitors enhance the ability of omega-3 fatty
acids to protect exenatide and facilitate its absorption in the
intestine.
[0036] In some embodiments, protease inhibitor inhibits the
function of peptidases. In one embodiment, protease inhibitors
enhance the ability of omega-3 fatty acids to protect the protein
of the present invention and facilitate its absorption in the
intestine. In some embodiments, the protease inhibitor of the
present invention is a protein. In some embodiments, protease
inhibitors comprise cysteine protease inhibitors, serine protease
inhibitors (serpins), trypsin inhibitors, threonine protease
inhibitors, aspartic protease inhibitors, metallo protease
inhibitors. In some embodiments, protease inhibitors comprise
suicide inhibitor, transition state inhibitor, or chelating
agents.
[0037] In one embodiment, the protease inhibitor is soybean trypsin
inhibitor (SBTI). In another embodiment, the protease inhibitor is
AEBSF-HCl. In another embodiment, the inhibitor is
(epsilon)-aminocaproic acid. In another embodiment, the inhibitor
is (alpha) 1-antichymotypsin. In another embodiment, the inhibitor
is antipain. In another embodiment, the inhibitor is antithrombin
III. In another embodiment, the inhibitor is (alpha) 1-antitrypsin
([alpha] 1-proteinase inhibitor). In another embodiment, the
inhibitor is APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride).
In another embodiment, the inhibitor is sprotinin. In another
embodiment, the inhibitor is benzamidine-HCl. In another
embodiment, the inhibitor is chymostatin. In another embodiment,
the inhibitor is DFP (diisopropylfluoro-phosphate). In another
embodiment, the inhibitor is leupeptin. In another embodiment, the
inhibitor is PEFABLOC.RTM. SC (4-(2-Aminoethyl)-benzenesulfonyl
fluoride hydrochloride). In another embodiment, the inhibitor is
PMSF (phenylmethyl sulfonyl fluoride). In another embodiment, the
inhibitor is TLCK (1-Chloro-3-tosylamido-7-amino-2-heptanone HCl).
In another embodiment, the inhibitor is TPCK
(1-Chloro-3-tosylamido-4-phenyl-2-butanone). In another embodiment,
the inhibitor is trypsin inhibitor from egg white (Ovomucoid). In
another embodiment, the inhibitor is trypsin inhibitor from
soybean. In another embodiment, the inhibitor is aprotinin. In
another embodiment, the inhibitor is pentamidine isethionate. In
another embodiment, the inhibitor is pepstatin.
[0038] In another embodiment, the inhibitor is guanidium. In
another embodiment, the inhibitor is alpha2-macroglobulin. In
another embodiment, the inhibitor is a chelating agent of zinc. In
another embodiment, the inhibitor is iodoacetate. In another
embodiment, the inhibitor is zinc. Each possibility represents a
separate embodiment of the present invention. In another
embodiment, the amount of protease inhibitor utilized in methods
and compositions of the present invention is 0.1 mg/dosage unit. In
another embodiment, the amount of protease inhibitor is 0.2
mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage
unit. In another embodiment, the amount is 0.4 mg/dosage unit. In
another embodiment, the amount is 0.6 mg/dosage unit. In another
embodiment, the amount is 0.8 mg/dosage unit. In another
embodiment, the amount is 1 mg/dosage unit. In another embodiment,
the amount is 1.5 mg/dosage unit. In another embodiment, the amount
is 2 mg/dosage unit. In another embodiment, the amount is 2.5
mg/dosage unit. In another embodiment, the amount is 3 mg/dosage
unit. In another embodiment, the amount is 5 mg/dosage unit. In
another embodiment, the amount is 7 mg/dosage unit. In another
embodiment, the amount is 10 mg/dosage unit. In another embodiment,
the amount is 12 mg/dosage unit. In another embodiment, the amount
is 15 mg/dosage unit. In another embodiment, the amount is 20
mg/dosage unit. In another embodiment, the amount is 30 mg/dosage
unit. In another embodiment, the amount is 50 mg/dosage unit. In
another embodiment, the amount is 70 mg/dosage unit. In another
embodiment, the amount is 100 mg/dosage unit.
[0039] In another embodiment, the amount of protease inhibitor is
0.1-1 mg/dosage unit. In another embodiment, the amount of protease
inhibitor is 0.2-1 mg/dosage unit. In another embodiment, the
amount is 0.3-1 mg/dosage unit. In another embodiment, the amount
is 0.5-1 mg/dosage unit. In another embodiment, the amount is 0.1-2
mg/dosage unit. In another embodiment, the amount is 0.2-2
mg/dosage unit. In another embodiment, the amount is 0.3-2
mg/dosage unit. In another embodiment, the amount is 0.5-2
mg/dosage unit. In another embodiment, the amount is 1-2 mg/dosage
unit. In another embodiment, the amount is 1-10 mg/dosage unit. In
another embodiment, the amount is 2-10 mg/dosage unit. In another
embodiment, the amount is 3-10 mg/dosage unit. In another
embodiment, the amount is 5-10 mg/dosage unit. In another
embodiment, the amount is 1-20 mg/dosage unit. In another
embodiment, the amount is 2-20 mg/dosage unit. In another
embodiment, the amount is 3-20 mg/dosage unit. In another
embodiment, the amount is 5-20 mg/dosage unit. In another
embodiment, the amount is 10-20 mg/dosage unit. In another
embodiment, the amount is 10-100 mg/dosage unit. In another
embodiment, the amount is 20-100 mg/dosage unit. In another
embodiment, the amount is 30-100 mg/dosage unit. In another
embodiment, the amount is 50-100 mg/dosage unit. In another
embodiment, the amount is 10-200 mg/dosage unit. In another
embodiment, the amount is 20-200 mg/dosage unit. In another
embodiment, the amount is 30-200 mg/dosage unit. In another
embodiment, the amount is 50-200 mg/dosage unit. In another
embodiment, the amount is 100-200 mg/dosage unit.
[0040] In another embodiment, the amount of protease inhibitor
utilized in methods and compositions of the present invention is
1000 k.i.u. (kallikrein inactivator units)/pill. In another
embodiment, the amount is 10 k.i.u./dosage units. In another
embodiment, the amount is 12 k.i.u./dosage unit. In another
embodiment, the amount is 15 k.i.u./dosage units. In another
embodiment, the amount is 20 k.i.u./dosage unit. In another
embodiment, the amount is 30 k.i.u./dosage units. In another
embodiment, the amount is 40 k.i.u./dosage unit. In another
embodiment, the amount is 50 k.i.u./dosage units. In another
embodiment, the amount is 70 k.i.u./dosage units. In another
embodiment, the amount is 100 k.i.u./dosage unit. In another
embodiment, the amount is 150 k.i.u./dosage unit. In another
embodiment, the amount is 200 k.i.u./dosage units. In another
embodiment, the amount is 300 k.i.u./dosage unit. In another
embodiment, the amount is 500 k.i.u./dosage units. In another
embodiment, the amount is 700 k.i.u./dosage units. In another
embodiment, the amount is 1500 k.i.u./dosage unit. In another
embodiment, the amount is 3000 k.i.u./dosage unit. In another
embodiment, the amount is 4000 k.i.u./dosage unit. In another
embodiment, the amount is 5000 k.i.u./dosage unit.
[0041] Each amount of protease inhibitor represents a separate
embodiment of the present invention.
[0042] In another embodiment, the protease targeted by the protease
inhibitor of methods and compositions of the present invention is a
serine protease. In another embodiment, the protease is trypsin. In
another embodiment, the protease is chymotrypsin. In another
embodiment, the protease is carboxypeptidase. In another
embodiment, the protease is aminopeptidase. In another embodiment,
the protease is any other protease that functions in the duodenum
or the small intestine. Each possibility represents a separate
embodiment of the present invention.
[0043] In another embodiment, compositions of the present invention
further comprise a substance that enhances absorption of the
exenatide through an intestinal mucosal barrier. Such a substance
is referred to herein as an "enhancer." As provided herein,
enhancers, when used together with omega-3 fatty acids, enhance the
ability of exenatide to be absorbed in the intestine.
[0044] In one embodiment, the enhancer is
didecanoylphosphatidylcholine (DDPC). In one embodiment, the
enhancer is a chelating agent such as ethylenediaminetetraacetic
acid (EDTA) or egtazic acid EGTA. In a preferred embodiment, EDTA
is sodium-EDTA. In some embodiments, the enhancer is NO donor. In
some embodiments, the enhancer is a bile acid, glycine-conjugated
form of a bile acid, or an alkali metal salt. In one embodiment,
absorption enhancement is achieved through utilization of a
combination of .alpha.-galactosidase and .beta.-mannanase. In some
embodiments, the enhancer is a fatty acid such as sodium caprate.
In one embodiment, the enhancer is sodium glycocholate. In one
embodiment, the enhancer is sodium salicylate. In one embodiment,
the enhancer is n-dodecyl-.beta.-D-maltopyranoside. In some
embodiments, surfactants serve as absorption enhancer. In one
embodiment, the enhancer is chitisan such as N,N,N-trimethyl
chitosan chloride (TMC).
[0045] In one embodiment, NO donors of the present invention
comprise
3-(2-Hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine,
N-ethyl-2-(1-ethyl-hydroxy-2-nitro sohydrazino)-ethanamine, or
S-Nitroso-N-acetylpenicillamine
[0046] In another embodiment, the bile acid is cholic acid. In
another embodiment, the bile acid is chenodeoxycholic acid. In
another embodiment, the bile acid is taurocholic acid. In another
embodiment, the bile acid is taurochenodeoxycholic acid. In another
embodiment, the bile acid is glycocholic acid. In another
embodiment, the bile acid is glycochenocholic acid. In another
embodiment, the bile acid is 3 beta-monohydroxychloric acid. In
another embodiment, the bile acid is lithocholic acid. In another
embodiment, the bile acid is 5 beta-cholanic acid. In another
embodiment, the bile acid is 3,12-diol-7-one-5 beta-cholanic acid.
In another embodiment, the bile acid is 3
alpha-hydroxy-12-ketocholic acid. In another embodiment, the bile
acid is 3 beta-hydroxy-12-ketocholic acid. In another embodiment,
the bile acid is 12 alpha-3 beta-dihydrocholic acid. In another
embodiment, the bile acid is ursodesoxycholic acid.
[0047] In one embodiment, the enhancer is a nonionic surfactant. In
one embodiment, the enhancer is a nonionic polyoxyethylene ether
surface active agent (e.g one having an HLB value of 6 to 19,
wherein the average number of polyoxyethylene units is 4 to 30). In
another embodiment, the enhancer is an anionic surface active
agent. In another embodiment, the enhancer is a cationic surface
active agent. In another embodiment, the enhancer is an ampholytic
surface active agent. In one embodiment, zwitteruionic surfactants
such as acylcarnitines serve as absorption enhancers.
[0048] In another embodiment, the amount of enhancer utilized in
methods and compositions of the present invention is 0.1 mg/dosage
unit. In another embodiment, the amount of enhancer is 0.2
mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage
unit. In another embodiment, the amount is 0.4 mg/dosage unit. In
another embodiment, the amount is 0.6 mg/dosage unit. In another
embodiment, the amount is 0.8 mg/dosage unit. In another
embodiment, the amount is 1 mg/dosage unit. In another embodiment,
the amount is 1.5 mg/dosage unit. In another embodiment, the amount
is 2 mg/dosage unit. In another embodiment, the amount is 2.5
mg/dosage unit. In another embodiment, the amount is 3 mg/dosage
unit. In another embodiment, the amount is 5 mg/dosage unit. In
another embodiment, the amount is 7 mg/dosage unit. In another
embodiment, the amount is 10 mg/dosage unit. In another embodiment,
the amount is 12 mg/dosage unit. In another embodiment, the amount
is 15 mg/dosage unit. In another embodiment, the amount is 20
mg/dosage unit. In another embodiment, the amount is 30 mg/dosage
unit. In another embodiment, the amount is 50 mg/dosage unit. In
another embodiment, the amount is 70 mg/dosage unit. In another
embodiment, the amount is 100 mg/dosage unit.
[0049] In another embodiment, the amount of enhancer is 0.1-1
mg/dosage unit. In another embodiment, the amount of enhancer is
0.2-1 mg/dosage unit. In another embodiment, the amount is 0.3-1
mg/dosage unit. In another embodiment, the amount is 0.5-1
mg/dosage unit. In another embodiment, the amount is 0.1-2
mg/dosage unit. In another embodiment, the amount is 0.2-2
mg/dosage unit. In another embodiment, the amount is 0.3-2
mg/dosage unit. In another embodiment, the amount is 0.5-2
mg/dosage unit. In another embodiment, the amount is 1-2 mg/dosage
unit. In another embodiment, the amount is 1-10 mg/dosage unit. In
another embodiment, the amount is 2-10 mg/dosage unit. In another
embodiment, the amount is 3-10 mg/dosage unit. In another
embodiment, the amount is 5-10 mg/dosage unit. In another
embodiment, the amount is 1-20 mg/dosage unit. In another
embodiment, the amount is 2-20 mg/dosage unit. In another
embodiment, the amount is 3-20 mg/dosage unit. In another
embodiment, the amount is 5-20 mg/dosage unit. In another
embodiment, the amount is 10-20 mg/dosage unit. In another
embodiment, the amount is 10-100 mg/dosage unit. In another
embodiment, the amount is 20-100 mg/dosage unit. In another
embodiment, the amount is 30-100 mg/dosage unit. In another
embodiment, the amount is 50-100 mg/dosage unit. In another
embodiment, the amount is 10-200 mg/dosage unit. In another
embodiment, the amount is 20-200 mg/dosage unit. In another
embodiment, the amount is 30-200 mg/dosage unit. In another
embodiment, the amount is 50-200 mg/dosage unit. In another
embodiment, the amount is 100-200 mg/dosage unit.
[0050] Each type and amount of enhancer represents a separate
embodiment of the present invention.
[0051] In another embodiment, compositions of the present invention
further comprise a coating that inhibits digestion of the
composition in the stomach of a subject.
[0052] In one embodiment, coating inhibits digestion of the
composition in the stomach of a subject. In one embodiment, the
coated dosage forms of the present invention release drug when pH
move towards alkaline range. In one embodiment, coating is a
monolayer, wherein in other embodiments coating applied in
multilayers. In one embodiment, coating is a bioadhesive polymer
that selectively binds the intestinal mucosa and thus enables drug
release in the attachment site. In one embodiment, the enteric
coating is an enteric film coating. In some embodiment, coating
comprises biodegradable polysaccharide, chitosan, aquateric
aqueous, aquacoat ECD, azo polymer, cellulose acetate phthalate,
cellulose acetate trimelliate, hydroxypropylmethyl cellulose
phthalate, gelatin, poly vinyl acetate phthalate, hydrogel,
pulsincap, or a combination thereof. In one embodiment, pH
sensitive coating will be used according to the desired release
site and/or profile as known to one skilled in the art.
[0053] In one embodiment, the coating is an enteric coating.
Methods for enteric coating are well known in the art, and are
described, for example, in Siepmann F, Siepmann J et al, Blends of
aqueous polymer dispersions used for pellet coating: importance of
the particle size. J Control Release 2005; 105(3): 226-39; and
Huyghebaert N, Vermeire A, Remon J P. In vitro evaluation of
coating polymers for enteric coating and human ileal targeting. Int
J Pharm 2005; 298(1): 26-37. Each method represents a separate
embodiment of the present invention.
[0054] In another embodiment, Eudragit.RTM., an acrylic polymer, is
used as the enteric coating. The use of acrylic polymers for the
coating of pharmaceutical preparations is well known in the art.
Eudragit Acrylic Polymers have been shown to be safe, and are
neither absorbed nor metabolized by the body, but rather are
eliminated.
[0055] In another embodiment, the coating is a gelatin coating. In
another embodiment, microencapsulation is used to protect the
exenatide against decomposition in the stomach. Methods for
applying a gelatin coating and for microencapsulation are well
known in the art. Each method represents a separate embodiment of
the present invention.
[0056] In another embodiment, the coating is a film-coating. In
another embodiment, the coating is ethylcellulose. In another
embodiment, the coating is a water-based dispersion of
ethylcellulose, e.g. hydroxypropylmethylcelullose (HPMC) E15. In
another embodiment, the coating is a gastro-resistant coatings,
e.g. a polymer containing carboxylic acid groups as a functional
moiety. In another embodiment, the coating is a monolithic matrix.
In another embodiment, the coating is a cellulose ether (e.g.
hypromellose (HPMC). Each type of coating represents a separate
embodiment of the present invention.
[0057] In another embodiment, a multiparticulate dosage forms is
used to inhibit digestion of the composition in the stomach.
[0058] Each type of coating, dosage form, etc, that inhibits
digestion of the composition in the stomach represents a separate
embodiment of the present invention.
[0059] In another embodiment, the present invention provides a
method for oral or rectal administration of a exenatide to a
subject, whereby a substantial fraction of the exenatide retains
its activity after absorption through an intestinal mucosal barrier
or rectal mucosal barrier of the subject, comprising administering
orally or rectally to the subject a pharmaceutical composition
comprising exenatide and a protease inhibitor, thereby orally or
rectally administering exenatide to a subject. In another
embodiment, the present invention provides a method for oral or
rectal administration of a exenatide to a subject, whereby a
substantial fraction of the exenatide retains its activity after
absorption through an intestinal mucosal barrier or rectal mucosal
barrier of the subject, comprising administering orally or rectally
to the subject a pharmaceutical composition comprising exenatide
and an omega-3 fatty acid.
[0060] In another embodiment, the present invention provides a
method for treating diabetes mellitus in a subject, comprising
administering orally or rectally to the subject a pharmaceutical
composition comprising an exenatide and an omega-3 fatty acid,
thereby treating diabetes mellitus.
[0061] In one embodiment, the diabetes mellitus is Type I diabetes.
In another embodiment, the diabetes mellitus is Type II diabetes.
In another embodiment, the diabetes mellitus is insulin-dependent
diabetes. In another embodiment, the diabetes mellitus is
non-insulin-dependent diabetes. In another embodiment, the diabetes
mellitus is any other type of diabetes known in the art. Each
possibility represents a separate embodiment of the present
invention.
[0062] In one embodiment, six treatments a day of the exenatide
composition are administered. In one embodiment, five treatments a
day of the exenatide composition are administered. In another
embodiment, four treatments a day of the exenatide composition are
administered. In another embodiment, three treatments a day of the
exenatide composition are administered. In another embodiment, two
treatments a day are administered. In another embodiment, four
treatments a day are administered. In another embodiment, one
treatment a day is administered. In another embodiment, more than
four treatments a day are administered. Each possibility represents
a separate embodiment of the present invention.
[0063] In another embodiment, following oral or rectal exenatide
administration to patients with type 2 diabetes, exenatide plasma
concentrations rise rapidly and reach median peak plasma
concentrations in 1.5-3 hours. In another embodiment, following
oral or rectal administration exenatide concentrations are
measurable for approximately 10 hours postdose.
[0064] In another embodiment, following 2 days of exenatide oral or
rectal administration a reduction in mean HbAlC is observed. In
another embodiment, following 3 days of exenatide oral or rectal
administration a reduction in mean HbAlC is observed. In another
embodiment, following 4 days of exenatide oral or rectal
administration a reduction in mean HbAlC is observed. In another
embodiment, following 5 days of exenatide oral or rectal
administration a reduction in mean HbAlC is observed.
[0065] In another embodiment, exenatide 20-300 mcg dosed
administered before a meal results in reduction in postprandial
glucose excursions. Additionally, the incidence of transient low
blood glucose was higher when patients received exenatide
administered after a meal. In another embodiment, exenatide 20-300
mcg should be administered within the 180 minute period before the
meal. In another embodiment, exenatide 20-300 mcg should be
administered within the 150 minute period before the meal. In
another embodiment, exenatide 20-300 mcg should be administered
within the 120 minute period before the meal. In another
embodiment, exenatide 20-300 mcg should be administered within the
90 minute period before the meal. In another embodiment, exenatide
20-300 mcg should be administered within the 60 minute period
before the meal. In another embodiment, exenatide 20-300 mcg should
be administered within the 30 minute period before the meal.
[0066] In another embodiment, Exenatide is indicated for treatment
of type 1 diabetes mellitus. In another embodiment, Exenatide is
indicated for treatment of type 2 diabetes mellitus (DM) in
combination with metformin, and/or sulfonylureas in patients who
have not achieved adequate glycemic control on maximally tolerated
doses. In another embodiment, Exenatide is indicated for treatment
of type 2 diabetes mellitus (DM) in combination with metformin. In
another embodiment, Exenatide is indicated for treatment of type 2
diabetes mellitus (DM) in combination with sulfonylureas. In
another embodiment, Exenatide of the invention is formulated in a
single dosage form in combination with a sulfonylurea. In another
embodiment, Exenatide of the invention is formulated in a single
dosage form in combination with metformin.
[0067] In another embodiment, Exenatide formulations of the present
invention are useful in view of their pharmacological properties.
In another embodiment, Exenatide formulations of the present
invention possess glucagon levels reduction activity. In another
embodiment, Exenatide formulations of the present invention
suppress glucagon secretion. In another embodiment, Exenatide
formulations of the present invention suppress glucagon secretion,
as evidenced by the ability to lower glucagon levels in animals and
humans. In another embodiment, Exenatide formulations of the
present invention are used to treat conditions or diseases that can
be alleviated by reducing glucagon levels and suppressing glucagon
secretion.
[0068] The compounds referenced above may form salts with various
inorganic and organic acids and bases. Such salts include salts
prepared with organic and inorganic acids, for example, HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4, trifluoroacetic acid, acetic
acid, formic acid, methanesulfonic acid, toluenesulfonic acid,
maleic acid, fumaric acid and camphorsulfonic acid. Salts prepared
with bases include ammonium salts, alkali metal salts, e.g., sodium
and potassium salts, and alkali earth salts, e.g., calcium and
magnesium salts. Acetate, hydrochloride, and trifluoroacetate salts
are preferred. The salts may be formed by conventional means, as by
reacting the free acid or base forms of the product with one or
more equivalents of the appropriate base or acid in a solvent or
medium in which the salt is insoluble, or in a solvent such as
water which is then removed in vacuo or by freeze-drying or by
exchanging the ions of an existing salt for another ion on a
suitable ion exchange resin.
Obesity and Hypernutrition
[0069] In another embodiment, Exenatide formulations of the present
invention are useful in preventing obesity. In another embodiment,
Exenatide formulations of the present invention are useful in
preventing excess adipose tissue. In another embodiment, Exenatide
formulations of the present invention are useful in preventing
health risks associated with enhanced food intake. In another
embodiment, Exenatide formulations of the present invention are
useful in preventing diseases associated with obesity such as Type
2 diabetes, increased cardiac risk, hypertension, atherosclerosis,
degenerative arthritis, and increased incidence of complications of
surgery involving general anesthesia. In another embodiment,
Exenatide formulations of the present invention are useful in
treating diseases associated with obesity such as Type 2 diabetes,
increased cardiac risk, hypertension, atherosclerosis, degenerative
arthritis, and increased incidence of complications of surgery
involving general anesthesia.
[0070] In another embodiment, Exenatide formulations of the present
invention are useful in reducing the risk of developing diseases
associated with obesity such as Type 2 diabetes, increased cardiac
risk, hypertension, atherosclerosis, degenerative arthritis, and
increased incidence of complications of surgery involving general
anesthesia.
[0071] In another embodiment, Exenatide formulations of the present
invention are useful in controlling body weight. In another
embodiment, Exenatide formulations of the present invention are
useful in maintaining body weight. In another embodiment, Exenatide
formulations of the present invention are useful in reducing food
intake. In another embodiment, Exenatide formulations of the
present invention are useful in reducing food intake in obese
subjects. In another embodiment, Exenatide formulations of the
present invention are useful in decreasing the plasma glucose
level. In another embodiment, Exenatide formulations of the present
invention are useful in decreasing the plasma lipid level. In
another embodiment, Exenatide formulations of the present invention
are useful in preventing hypernutrition. In another embodiment,
Exenatide formulations of the present invention are useful in
treating hypernutrition.
[0072] In another embodiment, it can be appreciated that an
effective means to reduce food intake is a major challenge and a
superior method of treatment would be of great utility. Such a
method, and compounds and compositions comprising Exenatide which
are useful therefore, have been invented and are described and
claimed herein. Any of the methods of the present invention may
utilize, in various embodiments, any of the compositions of the
present invention.
[0073] In another embodiment, the present invention provides a
composition for oral or rectal administration of exenatide,
comprising an exenatide protein and a protease inhibitor, whereby a
substantial fraction of the exenatide retains the enzymatic
activity after absorption through an intestinal mucosal barrier of
a subject. In another embodiment, the present invention provides a
composition for oral or rectal administration of exenatide,
comprising an exenatide protein and an enhancer, whereby a
substantial fraction of the exenatide retains the enzymatic
activity after absorption through an intestinal mucosal barrier of
a subject. In another embodiment, the present invention provides a
composition for oral or rectal administration of exenatide,
comprising an exenatide protein and an omega-3 fatty acid, whereby
a substantial fraction of the exenatide retains the enzymatic
activity after absorption through an intestinal mucosal barrier of
a subject.
[0074] In one embodiment, the present invention provides the use of
exenatide and a protease inhibitor in the manufacture of a
medicament for oral or rectal administration of exenatide to a
subject, whereby a substantial fraction of exenatide retains its
activity after absorption through an intestinal mucosal barrier of
the subject. In one embodiment, the present invention provides the
use of exenatide and an enhancer in the manufacture of a medicament
for oral or rectal administration of exenatide to a subject,
whereby a substantial fraction of exenatide retains its activity
after absorption through an intestinal mucosal barrier of the
subject. In one embodiment, the present invention provides the use
of exenatide and an omega-3 fatty acid in the manufacture of a
medicament for oral or rectal administration of exenatide to a
subject, whereby a substantial fraction of exenatide retains its
activity after absorption through an intestinal mucosal barrier of
the subject.
[0075] In one embodiment, the present invention provides the use of
an exenatide protein and a protease inhibitor in the manufacture of
a medicament for treating diabetes mellitus in a subject. In one
embodiment, the present invention provides the use of an exenatide
protein and an enhancer in the manufacture of a medicament for
treating diabetes mellitus in a subject. In one embodiment, the
present invention provides the use of an exenatide protein and an
omega-3 fatty acid in the manufacture of a medicament for treating
diabetes mellitus in a subject.
[0076] In another embodiment, different constituents of
compositions of the present composition are absorbed at different
rates from the intestinal lumen into the blood stream. The
absorption of the bile acid, in one embodiment, is significantly
faster than the absorption of exenatide.
[0077] For this reason, in another embodiment, a drug regimen
involving ingestion of a pair of pills at spaced intervals, e.g., a
second pill containing a higher concentration of enhancer is taken
at a defined interval (e.g. 30 minutes) after the first pill. In
another embodiment, certain of the constituents are
microencapsulated to enhance the absorption of the exenatide into
the system.
[0078] In one embodiment, a treatment protocol of the present
invention is therapeutic. In another embodiment, the protocol is
prophylactic. Each possibility represents a separate embodiment of
the present invention.
[0079] In another embodiment, the present invention provides oral
or rectal administration of exenatide which is comparable to
previous injectable dosage forms of exenatide. In another
embodiment, the present invention provides superior oral or rectal
administration of exenatide compared to previous injectable dosage
forms of exenatide. In another embodiment, oral or rectal
administration of exenatide is cheaper than injectable dosage forms
of exenatide. In another embodiment, oral or rectal administration
of exenatide provides better compliance than injectable dosage
forms of exenatide. In another embodiment, oral or rectal
administration of exenatide provides fewer side effects than
injectable dosage forms of exenatide.
[0080] In another embodiment, solid carriers/diluents for use in
methods and compositions of the present invention include, but are
not limited to, a gum, a starch (e.g. corn starch, pregeletanized
starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a
cellulosic material (e.g. microcrystalline cellulose), an acrylate
(e.g. polymethylacrylate), calcium carbonate, magnesium oxide,
talc, or mixtures thereof.
[0081] In another embodiment, the compositions further comprise
binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl
cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, povidone), disintegrating agents (e.g. cornstarch,
potato starch, alginic acid, silicon dioxide, croscarmellose
sodium, crospovidone, guar gum, sodium starch glycolate), buffers
(e.g., Tris-HCl, acetate, phosphate) of various pH and ionic
strength, additives such as albumin or gelatin to prevent
absorption to surfaces, detergents (e.g., Tween 20, Tween 80,
Pluronic F68, bile acid salts), protease inhibitors, surfactants
(e.g. sodium lauryl sulfate), permeation enhancers, solubilizing
agents (e.g., glycerol, polyethylene glycerol), anti-oxidants
(e.g., ascorbic acid, sodium metabisulfite, butylated
hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose,
hydroxypropylmethyl cellulose), viscosity increasing agents (e.g.
carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),
sweeteners (e.g. aspartame, citric acid), preservatives (e.g.,
Thimerosal, benzyl alcohol, parabens), lubricants (e.g. stearic
acid, magnesium stearate, polyethylene glycol, sodium lauryl
sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers
(e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g.
carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer
coatings (e.g., poloxamers or poloxamines), coating and film
forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates)
and/or adjuvants. Each of the above excipients represents a
separate embodiment of the present invention.
[0082] In some embodiments, the dosage forms of the present
invention are formulated to achieve an immediate release profile,
an extended release profile, or a delayed release profile. In some
embodiments, the release profile of the composition is determined
by using specific excipients that serve for example as binders,
disintegrants, fillers, or coating materials. In one embodiment,
the composition will be formulated to achieve a particular release
profile as known to one skilled in the art.
[0083] In another embodiment, the oral or rectal formulation of the
present invention is further formulated to accomplish sustained
release of Exenatide. In another embodiment, the oral or rectal
formulation of the present invention is further formulated to
accomplish immediate release of Exenatide. In another embodiment,
the oral or rectal formulation of the present invention is further
formulated to accomplish slow release of Exenatide. In another
embodiment, the oral or rectal formulation of the present invention
is further formulated to accomplish a combination of sustained and
immediate release of Exenatide. In another embodiment, the release
rate of Exenatide can be manipulated by various formulatory methods
known to one of skill in the art of the invention.
[0084] In one embodiment, the composition is formulated as an oral
dosage form. In one embodiment, the composition is a solid oral
dosage form comprising tablets, chewable tablets, suppositories, or
capsules. In one embodiment the capsules are soft gelatin
capsules.
[0085] In other embodiments, controlled- or sustained-release
coatings utilized in methods and compositions of the present
invention include formulation in lipophilic depots (e.g. fatty
acids, waxes, oils).
[0086] The compositions also include, in another embodiment,
incorporation of the active material into or onto particulate
preparations of polymeric compounds such as polylactic acid,
polglycolic acid, hydrogels, etc, or onto liposomes,
microemulsions, micelles, unilamellar or multilamellar vesicles,
erythrocyte ghosts, or spheroplasts.) Such compositions will
influence the physical state, solubility, stability, rate of in
vivo release, and rate of in vivo clearance. In another embodiment,
particulate compositions of the active ingredients are coated with
polymers (e.g. poloxamers or poloxamines)
[0087] In another embodiment, the compositions containing the
exenatide and omega-3 fatty acid are delivered in a vesicle, e.g. a
liposome (see Langer, Science 249:1527-1533 (1990); Treat et al.,
in Liposomes in the Therapy of Infectious Disease and Cancer,
Lopez--Berestein and Fidler (eds.), Liss, New York, pp. 353-365
(1989); Lopez-Berestein, ibid., pp. 317-327; see generally
ibid).
[0088] The preparation of pharmaceutical compositions that contain
an active component, for example by mixing, granulating, or
tablet-forming processes, is well understood in the art. The active
therapeutic ingredient is often mixed with excipients that are
pharmaceutically acceptable and compatible with the active
ingredient. For oral administration, the active ingredients of
compositions of the present invention are mixed with additives
customary for this purpose, such as vehicles, stabilizers, or inert
diluents, and converted by customary methods into suitable forms
for administration, such as tablets, coated tablets, hard or soft
gelatin capsules, aqueous, alcoholic or oily solutions.
[0089] In another embodiment, the formulation of the present
invention further comprises a base. In another embodiment, the base
used in the pharmaceutical composition of this invention may be
those which are known as bases of suppositories for intrarectal
administration. In some embodiments, base include oils and fats
comprising triglycerides as main companothernts such as cacao
butter, palm fat, palm kernel oil, coconut oil, fractionated
coconut oil, lard and WITEPSOL.RTM..TM., waxes such as lanolin and
reduced lanolin; hydrocarbons such as Vaseline, squalene, squalane
and liquid paraffin; long to medium chain fatty acids such as
caprylic acid, lauric acid, stearic acid and oleic acid; higher
alcohols such as lauryl alcohol, cetanol and stearyl alcohol; fatty
acid esters such as butyl stearate and dilauryl malonate; medium to
long chain carboxylic acid esters of glycerin such as triolein and
tristearin; glycerin-substituted carboxylic acid esters such as
glycerin acetoacetate; and polyethylene glycols and its derivatives
such as macrogols and cetomacrogol. They may be used either singly
or in combination of two or more.
[0090] In some embodiments, the composition of this invention may
further include a surface-active agent, preservative, and coloring
agent, which are ordinarily used in suppositories.
[0091] In another embodiment, the unit dosage forms of the
pharmaceutical composition of this invention include a solid
suppository having as a base a solid fat which when administered to
the rectum, becomes flowable within the rectum, such as cacao
butter and WITEPSOL, a solid suppository having as a base a
hydrophilic solid substance which becomes flowable in the rectum in
the same way, such as macrogol, and a gelatin capsule suppository
having a normally liquid substance (liquid at room temperature)
such as neutral fatty acid triglycerides and vegetable oils as a
base and coated with a gelatin film.
[0092] Each of the above additives, excipients, formulations and
methods of administration represents a separate embodiment of the
present invention.
[0093] In one embodiment, the term "treating" refers to curing a
disease. In another embodiment, "treating" refers to preventing a
disease. In another embodiment, "treating" refers to reducing the
incidence of a disease. In another embodiment, "treating" refers to
ameliorating symptoms of a disease. In another embodiment,
"treating" refers to inducing remission. In another embodiment,
"treating" refers to slowing the progression of a disease.
Experimental Details Section
Animals
[0094] Male beagle dogs weighing about 9 kg were used for all
experiments described hereinbelow.
Example 1
Protection of Exenatide from Proteases and Successful
Administration Via the Duodenum in Dogs
Materials and Experimental methods
Formulations
[0095] (1) A formulation containing 150 milligram (mg) Na-EDTA
(Sigma-Aldrich, St. Louis, Mo.), 125 mg soybean trypsin inhibitor
(SBTI; Sigma), 50 .mu.g exenatide, and 0.8 milliliter (ml) fish oil
was prepared.
[0096] A formulation containing 150 milligram (mg) Na-EDTA
(Sigma-Aldrich, St. Louis, Mo.), 125 mg soybean trypsin inhibitor
(SBTI; Sigma), 100 .mu.g exenatide, and 0.8 milliliter (ml) fish
oil was prepared.
[0097] (3) A formulation containing 150 milligram (mg) Na-EDTA
(Sigma-Aldrich, St. Louis, Mo.), 125 mg soybean trypsin inhibitor
(SBTI; Sigma), 0.8 milliliter (ml) fish oil was prepared.
Results
[0098] To test whether exenatide can be protected from proteases
and absorbed via the duodenum, formulation 1 (treatment) or 3
(control) were administered directly to the duodenum of about 9 kg
beagle dogs or by an endoscope to about 16 kg pigs.
[0099] All dogs and pigs were administered 40 ml of 50% glucose
solution. Blood glucose was measured every 5 minutes following
administration. As depicted below in Table 1, blood glucose levels
were significantly reduced in response to exenatide.
[0100] The ability of formula 1 to substantially reduce blood
glucose levels is also shown in FIG. 1 in dogs. Similar results
were obtained in pigs. Moreover, FIG. 3 shows that an oral dosage
form of Exendin-4 can replace injectable dosage forms of
Exendin-4(see Example 2) in reducing blood glucose levels.
TABLE-US-00001 TABLE 1 Blood glucose concentrations following
administration of exenatide to the duodenum in experiment #1.
Glucose in milligrams/deciliter Glucose in milligrams/deciliter
(mg/dL) in dogs treated with (mg/dL) in dogs treated with Time
(min) formulation 1-Treatment formulation 3-Control 0 69 69 10 93
97 20 89 131 30 93 159 40 111 156 50 94 139 60 103 134 70 104 112
80 118 117 90 105 84 100 90 88 110 94 80 120 92 73
[0101] Thus, oral compositions comprising a protease inhibitor and
Na-EDTA can protect exenatide from proteases in the small intestine
and enable direct absorption of orally administered exenatide.
Example 2
Injectable Dosage Forms Compared to Rectal and Oral Dosage
Forms
Materials and Experimental Methods
Formulation
[0102] The following formulations were prepared: [0103] (1) An
injectable formulation comprising 2.5 .mu.g commercial byetta.
[0104] (2) An injectable formulation comprising 2.5 .mu.g
GeneScript (Piscataway, N.J.) byetta. [0105] (3) An oral
formulation containing 150 milligram (mg) Na-EDTA (Sigma-Aldrich,
St. Louis, Mo.), 125 mg soybean trypsin inhibitor (SBTI; Sigma), 50
.mu.g exenatide (GeneScript (Piscataway, N.J.)) and 0.8 milliliter
(nil) fish oil. [0106] (4) An oral formulation containing 150
milligram (mg) Na-EDTA (Sigma-Aldrich, St. Louis, Mo.), 125 mg
soybean trypsin inhibitor (SBTI; Sigma), 0.8 milliliter (ml) fish
oil. [0107] (5) A hard gelatin capsule (rectal) containing 150
milligram (mg) Na-EDTA (Sigma-Aldrich, St. Louis, Mo.), 125 mg
soybean trypsin inhibitor (SBTI; Sigma), 50 .mu.g exenatide
(GeneScript (Piscataway, N.J.)) and in 0.8 milliliter (ml) fish
oil.
Results
[0108] To test the effectiveness of oral and rectal formulations
comprising exenatide, oral and rectal formulations were compared to
commercially available injectable formulations.
[0109] All dogs were administered 40 ml of 50% glucose solution.
Blood glucose was measured every 5 minutes following
administration.
[0110] The results obtained show that oral (FIGS. 1 and 3) and
rectal (FIG. 2) dosage forms comprising Exendin-4 are can
unexpectedly replace injectable dosage forms comprising Exendin-4
in terms of controlling blood glucose levels for 2 hours after
glucose load.
[0111] These results further confirm the results of Example 1,
showing that compositions comprising a protease inhibitor and
Na-EDTA can protect exenatide from proteases in the small intestine
and enable direct absorption of orally administered exenatide.
[0112] The Exendin-4-used for the oral and rectal dosage forms was
obtained from GeneScript. The results presented (FIGS. 2 and 4)
show that Exendin-4-purchased from GeneScript is effective as the
commercial Exendin-4(Eli Lilly, USA). In conclusion, the oral
and/or rectal routes of administration are favorable over the
injectable route of administration for many reasons that are known
to one of skill in the art. The unexpected results presented herein
demonstrate the ability to effectively administer Exendin-4-via an
oral or rectal route of administration.
Example 3
Enteral Administration of Exenatide-4; Proof of Concept
Pharmacodynamic Study in Dogs with a Formulation Which Facilitates
the Absorption of Exenatide-4 Across Biological Membranes
Materials and Experimental Methods
[0113] Study was conducted in 4 beagle dogs with an average weight
of 10 kg. All the dogs had a cannula residing in the jejunum
through which the drug was administered. After an overnight fast,
the dogs were given different doses of oral GLP-1 analogue or sc
injection of the analogue. Absorption of the GLP-1 analogue was
assessed by measuring the effect on glucose excursion following an
oral glucose load. Control experiment consisted of oral dosing
without administration of GLP-1 analogue. The interval between oral
administration and the oral glucose load was 30 minutes. The
primary efficacy end point was the glucose excursion above the
pre-OGTT glucose level over a 150 min interval (incremental area
under the curve (AUC).sub.0-150 min).
Results
[0114] Direct jejunal instillation of GLP-1 analogue significantly
(ss) curbed glucose excursion, post glucose load (both in
comparison to placebo and among the separate groups)
[0115] Results are shown in Table 2 and FIG. 4.
TABLE-US-00002 TABLE 2 OGTT-Glucose AUC.sub.0-150 min Mean .+-. SD
Placebo 8906 .+-. 1508 GLP-1 2.5 .mu.g sc 3656 .+-. 510 GLP-1 75
.mu.g PO 6292 .+-. 1043 GLP-1 100 .mu.g PO 5085 .+-. 931
[0116] Oral delivery of proteins and peptide drugs remains a major
challenge because of their unique physico-chemical and biologic
properties. As demonstrated herein the presented proprietary
technology can effectively and reliably transport macromolecules
including polypeptides and proteins such as exenatide across
biological membranes. Moreover, unexpectedly, the native compound
retained its biological activity on reaching the systemic
circulation.
[0117] Specifically, in the current study in dogs the results
clearly demonstrate that an oral GLP-1 analogue, exenatide, when
administered before a meal can blunt meal induced glycemic
excursion by about 40% as compared to parenteral exenatide 50%
blunting capacity. Pd effects are commonly used in a
semi-quantitative way to establish GLP-1 levels in studies
assessing DPP IV inhibition. In this study it have been
unexpectedly demonstrated that the GLP-1 analogue exenatide can be
created in an oral dosage form and that it could be ingested by the
patient shortly before a meal. These two qualities in a drug
significantly facilitate its acceptance among patients and foster
higher patient compliance and adherence to the medication.
[0118] The results of this study in dogs showed that GLP-1 analogue
exenatide when combined with the delivery enhancers and formulated
in a capsule is absorbed and results in significant blunting of
glucose excursion after an oral OGTT. The Pharmacodynamic response
to oral exenatide ingestion was robust and reproducible and the
short interval between capsule ingestion and meal suggests that a
practical and patient friendly oral dosage form can be created. As
of now the only incretin mimetics available as oral medication are
the DPP IV inhibitors. An oral dosage form of GLP-1 analogues will
broaden the choice of available drugs from this important class of
antihyperglycemic medication.
Example 4
Oral Administration of Pills Containing Exenatide and a Protease
Inhibitor
Preparation of Tablet Cores
[0119] Tablet cores comprising exenatide and a protease inhibitor
are prepared using methods well known in the art.
Coating
[0120] The coating may be any delayed release coating known in the
art. For example, the coating may be a polymer composed of the
following ingredients:
[0121] 4 mg Eudragit L-100 (Polymer of Acrylic and Methacrylic Acid
Esters)
[0122] 4 mg Talc NF
[0123] 0.4 mg Polyethylene Glycol 6000 NF
[0124] In one embodiment, a solution of the enteric coated polymer
is prepared by dissolving the polymer in a methylene
chloride+isopropyl alcohol mixture. The tablets are coated by
spraying the solution within a mildly warmed jar under constant
agitation. The solvent vapors are continuously aspirated.
Measurement of Levels and Activity of Recombinant Exenatide in
Subjects' Plasma
[0125] Levels of C peptide are measured as well, to determine the
relative contributions of endogenous and exogenous exenatide to
observed rises in exenatide levels.
Results
[0126] A mixture of Na-EDTA, SBTI, and exenatide and fish oil is
formulated into tablet or capsule cores, coated with an enteric
coating or gelatin coating, and administered to human subjects.
Blood glucose levels of the subjects are measured periodically as
described in the previous Examples. In addition, the subjects'
plasma levels of recombinant exenatide and its activity are tested.
The coated pills are shown to deliver functional exenatide to the
subjects, and the exenatide significantly lowers their blood
glucose levels, showing that active exenatide can be delivered to
the bloodstream via oral administration. Different types of
commercially available delayed release coatings are tested to
determine which coating provides the best delivery of exenatide,
and this coating is used in subsequent Examples.
Example 5
Optimization of Source of Omega-3 Fatty Acids
[0127] Various omega-3 fatty acids or sources of omega-3 fatty
acids (e.g. those listed above in the specification) are compared
for their ability to preserve exenatide following oral
administration in methods and compositions of the present
invention. Exenatide tablets or capsules are formulated as
described in the above Examples, except that the exenatide is
combined with alternate source instead of in fish oil. The most
effective source of omega-3 fatty acids is used in subsequent
Examples.
Example 6
Optimization of Protease Inhibitors
[0128] Various protease inhibitors (either non-toxic or having an
acceptable toxicity profile; e.g. those listed above in the
specification) are compared for their ability to preserve exenatide
following oral administration in methods and compositions of the
present invention. Exenatide tablets or capsules are formulated as
described in the above Examples, except that the alternate protease
inhibitors are substituted for SBTI. Amounts of the protease
inhibitors are also varied, to determine the optimal amounts. The
most effective protease inhibitor/amount is used in subsequent
Examples.
Example 7
Optimization of Enhancer
[0129] Various enhancers (e.g. those listed above in the
specification) are compared for their ability to facilitate
absorption of exenatide following oral administration in methods
and compositions of the present invention. Exenatide tablets or
capsules are formulated as described in the above Examples, except
that the alternate enhancers are substituted for EDTA. Amounts of
the enhancers are also varied, to determine the optimal amounts.
The most effective enhancer/amount is used in subsequent
experiments.
Example 8
Optimization of Type and Amount of Exenatide
[0130] Various types and amounts of exenatide e.g. those listed
above in the specification) are compared for their ability to
regulate blood sugar in methods and compositions of the present
invention. Exenatide tablets or capsules are formulated as
described in the above Examples, except that the type and amount of
exenatide is varied. The most effective type/amount of exenatide is
used in clinical trials.
Sequence CWU 1
1
1139PRTHeloderma suspectum 1His Gly Glu Gly Thr Phe Thr Ser Asp Leu
Ser Lys Gln Met Glu Glu1 5 10 15Glu Ala Val Arg Leu Phe Ile Glu Trp
Leu Lys Asn Gly Gly Pro Ser 20 25 30Ser Gly Ala Pro Pro Pro Ser
35
* * * * *