U.S. patent application number 11/144580 was filed with the patent office on 2005-12-22 for oral delivery of peptide pharmaceutical compositions.
Invention is credited to Gilligan, James P., Mehta, Nozer M., Stern, William.
Application Number | 20050282756 11/144580 |
Document ID | / |
Family ID | 35481400 |
Filed Date | 2005-12-22 |
United States Patent
Application |
20050282756 |
Kind Code |
A1 |
Mehta, Nozer M. ; et
al. |
December 22, 2005 |
Oral delivery of peptide pharmaceutical compositions
Abstract
Bioavailability of peptide active agents to be administered
orally is enhanced by a pharmaceutical composition providing
targeted release of the peptide to the intestine by combining the
composition with an absorption enhancer. Bioavailability is further
significantly increased by administering the composition in an
acid-resistant protective vehicle which transports components of
the invention through the stomach. The composition may optionally
further include a sufficient amount of a pH-lowering agent to lower
local intestinal pH. All components are released together into the
intestine with the peptide.
Inventors: |
Mehta, Nozer M.; (Randolph,
NJ) ; Stern, William; (Tenafly, NJ) ;
Gilligan, James P.; (Union, NJ) |
Correspondence
Address: |
OSTROLENK FABER GERB & SOFFEN
1180 AVENUE OF THE AMERICAS
NEW YORK
NY
100368403
|
Family ID: |
35481400 |
Appl. No.: |
11/144580 |
Filed: |
June 2, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60580872 |
Jun 18, 2004 |
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Current U.S.
Class: |
514/1.3 ;
514/12.1; 514/16.4; 514/18.3; 514/18.4 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 9/4891 20130101; A61K 47/26 20130101; A61K 38/08 20130101;
A61K 9/0095 20130101; A61K 38/06 20130101; A61K 47/183 20130101;
A61P 9/00 20180101; A61K 9/0053 20130101; A61K 38/07 20130101; A61K
9/4858 20130101 |
Class at
Publication: |
514/017 |
International
Class: |
A61K 038/06 |
Claims
What is claimed is:
1. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a dermorphin analog or a prodrug thereof, wherein said
dermorphin analog is a peptide of formula I 7wherein R.sup.1 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.7
branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl,
benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl,
carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl,
chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and
nitrobenzyl; R.sup.2 is hydrogen, methyl, ethyl; or R.sup.1 and
R.sup.2, taken together with the carbon atom to which they are
attached, form a cycloalkyl ring containing 3-5 carbon atoms; X is
selected from the group consisting of C.dbd.O, N--H, CH.sub.2,
--O--, C.dbd.S and --S--; Y is selected from the group C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and Y, taken
together, represent an olefin linkage wherein X and Y each have a
hydrogen atom attached thereto in a cis or trans configuration; and
n is 1-7; and (B) at least one absorption enhancer effective to
promote bioavailability of said dermorphin analog or prodrug
thereof.
2. The pharmaceutical composition of claim 1, which further
comprises at least one additional component selected from the group
consisting of: (C) an acid-resistant protective vehicle effective
to transport said pharmaceutical composition through the stomach of
a patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (D) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of said solution to no higher than 5.5.
3. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a dermorphin analog or a prodrug thereof, wherein said
dermorphin analog is a peptide of formula I 8wherein R.sup.1 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.7
branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl,
benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, am idobenzyl,
carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl,
chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and
nitrobenzyl; R.sup.2 is hydrogen, methyl, ethyl; or R.sup.1 and
R.sup.2, taken together with the carbon atom to which they are
attached, form a cycloalkyl ring containing 3-5 carbon atoms; X is
selected from the group consisting of C.dbd.O, N--H, CH.sub.2,
--O--, C.dbd.S and --S--; Y is selected from the group C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and Y, taken
together, represent an olefin linkage wherein X and Y each have a
hydrogen atom attached thereto in a cis or trans configuration; and
n is 1-7; (B) at least one absorption enhancer effective to promote
bioavailability of said dermorphin analog or prodrug thereof; and
(C) an acid resistant protective vehicle effective to transport
said pharmaceutical composition through the stomach of a patient
while preventing contact between said pharmaceutical composition
and stomach proteases.
4. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a dermorphin analog or a prodrug thereof, wherein said
dermorphin analog is a peptide of formula I 9wherein R.sup.1 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.7
branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl,
benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl,
carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl,
chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and
nitrobenzyl; R.sup.2 is hydrogen, methyl, ethyl; or R.sup.1 and
R.sup.2, taken together with the carbon atom to which they are
attached, form a cycloalkyl ring containing 3-5 carbon atoms; X is
selected from the group consisting of C.dbd.O, N--H, CH.sub.2,
--O--, C.dbd.S and --S--; Y is selected from the group C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and Y, taken
together, represent an olefin linkage wherein X and Y each have a
hydrogen atom attached thereto in a cis or trans configuration; and
n is 1-7; and (B) at least one pharmaceutically acceptable
pH-lowering agent, wherein said pH-lowering agent is present in
said pharmaceutical composition in a quantity which, if said
composition were added to 10 milliliters of 0.1M aqueous sodium
bicarbonate solution, would be sufficient to lower the pH of said
solution to no higher than 5.5.
5. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof
said composition comprising: (A) a therapeutically effective amount
of a dermorphin analog or a prodrug thereof, wherein said
dermorphin analog is a peptide of formula I 10wherein R.sup.1 is
selected from the group consisting of hydrogen, C.sub.1-C.sub.7
branched or unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl,
benzyl, hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl,
carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl,
chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and
nitrobenzyl; R.sup.2 is hydrogen, methyl, ethyl; or R.sup.1 and
R.sup.2, taken together with the carbon atom to which they are
attached, form a cycloalkyl ring containing 3-5 carbon atoms; X is
selected from the group consisting of C.dbd.O, N--H, CH.sub.2,
--O--, C.dbd.S and --S--; Y is selected from the group C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and Y, taken
together, represent an olefin linkage wherein X and Y each have a
hydrogen atom attached thereto in a cis or trans configuration; and
n is 1-7; (B) at least one pharmaceutically acceptable pH-lowering
agent; and (C) at least one absorption enhancer effective to
promote bioavailability of said dermorphin analog or prodrug
thereof, wherein said pH-lowering agent is present in said
pharmaceutical composition in a quantity which, if said composition
were added to ten milliliters of 0.1M aqueous sodium bicarbonate
solution, would be sufficient to lower the pH of said solution to
no higher than 5.5.
6. The pharmaceutical composition of claim 1, wherein said
dermorphin analog is a peptide selected from the group represented
by the formulae: (A)
H-Tyrosine-D-Norvaline-Phenylalanine-Ornithine-NH.sub.2; (B)
H-Tyrosine-D-Norleucine-Phenylalanine-Ornithine-NH.sub.2; (C)
H-Tyrosine-D-Arginine-Phenylalanine-.alpha.,.gamma.-diaminobutyric
acid-NH.sub.2; (D)
H-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2; (E)
H-Lysine-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2; and (F)
N'-amidino-Tyrosine-D-arginine-Phenylalanine-Methyl-.alpha.-alanine-OH,
or analogs thereof.
7. The pharmaceutical composition of claim 1, wherein the
dermorphin analog is a peptide of formula II
H-Tyrosine-A-Phenylalanine-B-NH.sub.2 wherein: A is selected from
the group consisting of D-.alpha.-amino acids; B is selected from
the group consisting of .alpha.-amino acids; and an overall net
positive charge of the peptide is +2 or greater.
8. The pharmaceutical composition of claim 7, wherein A is selected
from the group consisting of D-norvaline, D-norleucine, D-arginine,
D-alanine, D-valine, D-isoleucine, D-leucine, D-serine,
D-phenylalanine and D-.alpha.,.gamma.-diaminobutyric acid.
9. The pharmaceutical composition of claim 7, wherein B is selected
from the group consisting of phenylalanine, para-fluoro
phenylalanine, ornithine, .alpha.,.gamma.-diaminobutyric acid,
lysine, norvaline, arginine, .alpha.,.beta.-diaminopropionic acid
and homolysine.
10. The pharmaceutical composition of claim 7, wherein the overall
net positive charge of the peptide is +2 or +3.
11. The pharmaceutical composition of claim 1, wherein said
dermorphin analog is an opioid peptide of formula III wherein
R.sup.1 is selected from (i) linear or branched C.sub.1-C.sub.6
alkyl; (ii) C.sub.1-C.sub.6 alkoxy; R.sup.2 is selected from (i)
hydrogen; (ii) linear or branched C.sub.1-C.sub.6 alkyl; (iii)
C.sub.1-C.sub.6 alkoxy; R.sup.3 and R.sup.4 is each and
independently selected from (i) hydrogen; 11(ii) linear or branched
C.sub.1-C.sub.6 alkyl; 12R.sup.5, R.sup.6, R.sup.7, R.sup.8 and
R.sup.9 is each independently selected from (i) hydrogen; (ii)
halogen, where "halogen" encompasses chloro, fluoro, bromo and
iodo; and (iii) linear or branched C.sub.1-C.sub.6 alkyl; and n is
an integer of from 1 to 5, and wherein the composition further
comprises (A) an acid-resistant protective vehicle effective to
transport said pharmaceutical composition through the stomach of a
patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (B) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of said solution to no higher than 5.5.
12. The pharmaceutical composition of claim 11, wherein: R.sup.1 is
a linear C.sub.1-C.sub.6 alkyl; R.sup.2 is a linear C.sub.1-C.sub.6
alkyl or hydrogen; R.sup.3 and R.sup.4 is each and independently
selected from a straight C.sub.1-C.sub.6 alkyl or hydrogen;
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is each and
independently selected from (i) hydrogen; (ii) a halogen selected
from chloro, fluoro, bromo and iodo; and (iii) linear or branched
C.sub.1-C.sub.6 alkyl, and n is an integer from 1 to 5.
13. The pharmaceutical composition of claim 11, wherein: R.sup.1 is
CH.sub.3; R.sup.2 is hydrogen or CH.sub.3; R.sup.3 and R.sup.4 are
both hydrogen; R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are
all hydrogen; and n=4.
14. The pharmaceutical composition of claim 11, wherein said
dermorphin analog is a peptide represented by the formula:
H-2,6-dimethyltyrosine-D--
Arginine-Phenylalanine-Lysine-NH.sub.2
15. The pharmaceutical composition of claim 1, wherein said
dermorphin analog is a peptide of formula IV:
Tyrosine-D-alanine-Xaa-Glycine-Tyrosin- e-Proline-Serine-NH.sub.2
wherein Xaa is L- or D-dimethylphenylalanine.
16. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a deltorphin analog or a prodrug thereof, wherein said
deltorphin analog is a peptide of formula V:
Tyrosine-D-alanine-Xaa-Glutamic Acid-Valine-Valine-Glycine-NH.sub.2
wherein Xaa is L-or D-dimethylphenylalanine; and (B) at least one
absorption enhancer effective to promote bioavailability of said
deltorphin analog or prodrug thereof.
17. The pharmaceutical composition of claim 16, which further
comprises at least one additional component selected from the group
consisting of: (C) an acid-resistant protective vehicle effective
to transport said pharmaceutical composition through the stomach of
a patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (D) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of said solution to no higher than 5.5,
18. A pharmaceutical composition for oral delivery of a compound
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a compound which is an agonist or partial agonist of vanilloid
receptor VR1; and (B) at least one absorption enhancer effective to
promote bioavailability of said compound.
19. The pharmaceutical composition of claim 18, which further
comprises at least one additional component selected from the group
consisting of: (C) an acid-resistant protective vehicle effective
to transport said pharmaceutical composition through the stomach of
a patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (D) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of said solution to no higher than 5.5.
20. The pharmaceutical composition of claim 19 wherein said
compound is selected from the group consisting of: (i)
N-[2-(3,4-dimethylbenzyl)-3-(p-
ivaloyloxy)propyl]-N'-[4-(methylsulfonylamino)benzyl]thiourea; and
(ii)
N-(4-tert-butylbenzyl)-N'-[3-methoxy-4-(methylsulfonylamino)benzyl]thiour-
ea.
21. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of an enkephalin peptide or a prodrug thereof, wherein said
enkephalin peptide is a peptide selected from the group represented
by the formulae (i)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH; (ii)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH; (iii)
H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol; and
(iv) analogs thereof; and (B) at least one absorption enhancer
effective to promote bioavailability of said enkephalin peptide or
prodrug thereof.
22. The pharmaceutical composition of claim 21, which further
comprises at least one additional component selected from the group
consisting of: (C) an acid-resistant protective vehicle effective
to transport said pharmaceutical composition through the stomach of
a patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (D) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of said solution to no higher than 5.5.
23. A pharmaceutical composition for oral delivery of a peptide
having analgesic or cardiovascular activity, or a prodrug thereof,
said composition comprising: (A) a therapeutically effective amount
of a peptide linked to a DMT-Tic-Pharmacophore having the structure
H-2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid, said peptide selected from the group consisting of (i)
H-DMT-Tic-Glycine-NH-Benzyl; and (ii)
H-DMT-Tic-NH--CH(CH.sub.2--COOH)-1-- H-benzimidazole-2-yl; and (B)
at least one absorption enhancer effective to promote
bioavailability of said peptide or prodrug thereof.
24. The pharmaceutical composition of claim 23, which further
comprises at least one additional component selected from the group
consisting of: (C) an acid-resistant protective vehicle effective
to transport said pharmaceutical composition through the stomach of
a patient while preventing contact between said pharmaceutical
composition and stomach proteases; and (D) at least one
pharmaceutically acceptable pH-lowering agent, wherein said
pH-lowering agent is present in said pharmaceutical composition in
a quantity which, if said composition were added to 10 milliliters
of 0.1 M aqueous sodium bicarbonate solution, would be sufficient
to lower the pH of said solution to no higher than 5.5.
25. The pharmaceutical composition of claim 1, wherein the
absorption enhancer is an acyl carnitine.
26. The pharmaceutical composition of claim 11, wherein the
absorption enhancer is an acyl carnitine.
27. The pharmaceutical composition of claim 25, further including a
sucrose ester.
28. The pharmaceutical composition of claim 26, further including a
sucrose ester.
29. The pharmaceutical composition of claim 1, further comprising
an amount of a second peptide, that is not a physiologically active
peptide, effective to enhance bioavailability of said peptide
having analgesic or cardiovascular activity or prodrug thereof.
30. The pharmaceutical composition of claim 11, further comprising
an amount of a second peptide, that is not a physiologically active
peptide, effective to enhance bioavailability of said peptide
having analgesic or cardiovascular activity or prodrug thereof.
31. The pharmaceutical composition of claim 1, further comprising a
water-soluble barrier that separates said pH-lowering agent from
said protective vehicle.
32. The pharmaceutical composition of claim 11, further comprising
a water-soluble barrier that separates said pH-lowering agent from
said protective vehicle.
33. The pharmaceutical composition of claim 1, wherein said
pharmaceutical composition comprises granules containing a
pharmaceutical binder and, uniformly dispersed in said binder, at
least one of said pH-lowering agent, said absorption enhancer and
said peptide having analgesic or cardiovascular activity, or
prodrug thereof.
34. The pharmaceutical composition of claim 11, wherein said
pharmaceutical composition comprises granules containing a
pharmaceutical binder and, uniformly dispersed in said binder, at
least one of said pH-lowering agent, said absorption enhancer and
said peptide having analgesic or cardiovascular activity, or
prodrug thereof.
35. The pharmaceutical composition according to claim 2, wherein
said acid resistant protective vehicle is a viscous protective
syrup.
36. The pharmaceutical composition of claim 11, wherein said acid
resistant protective vehicle is a viscous protective syrup.
37. A method for enhancing the bioavailability of a peptide having
analgesic or cardiovascular activity or a prodrug thereof delivered
orally, said method comprising selectively releasing said peptide
or prodrug thereof with at least one absorption enhancer into a
patient's intestine following passage of said peptide or prodrug
and said at least one absorption enhancer through said patient's
mouth and stomach.
38. The method of claim 37, wherein the passage of said peptide or
prodrug thereof and said at least one absorption enhancer through
said patient's mouth and stomach is under the protection of an
acid-resistant protective vehicle which prevents contact between
stomach proteases and said peptide or prodrug thereof.
39. The method of claim 37, wherein said peptide or prodrug thereof
and said at least one absorption enhancer are released into the
patient's intestine in the presence of at least one pH-lowering
agent, wherein said pH-lowering agent and other compounds released
therewith are released into said intestine in a quantity which, if
added to 10 milliliters of 0.1 M aqueous sodium bicarbonate
solution, would be sufficient to lower pH of said solution to no
higher than 5.5.
40. A method for enhancing the bioavailability of a peptide having
analgesic or cardiovascular activity or a prodrug thereof delivered
orally, said method comprising selectively releasing said peptide
or prodrug thereof, together with at least one pH-lowering agent
and at least one absorption enhancer, into a patient's intestine
following passage of said peptide or prodrug thereof, pH-lowering
agent and absorption enhancer through said patient's mouth and
stomach under protection of an acid-resistant protective vehicle
which substantially prevents contact between stomach proteases and
said peptide or prodrug thereof, wherein said pH-lowering agent and
other compounds released therewith are released into said intestine
in a quantity which, if added to 10 milliliters of 0.1M aqueous
sodium bicarbonate solution, would be sufficient to lower the pH of
said solution to no higher than 5.5.
41. The method of claim 37, wherein said absorption enhancer is
selected from the group consisting of a cationic surfactant and an
anionic surfactant that is a cholesterol derivative.
42. The method of claim 37, wherein said pH-lowering agent has a
pKa no higher than 4.2 and a solubility in water of at least 30
grams per 100 milliliters of water at room temperature
43. The method of claim 37, wherein a weight ratio of said
pH-lowering agent to said absorption enhancer is between 3:1 and
20:1.
44. The method of claim 37, wherein said pH-lowering agent is
present in an amount of not less than 300 milligrams.
45. A method for stimulating a mu, delta, or kappa-opioid receptor
in a mammal in need thereof, the method comprising orally
administering to the mammal an effective amount of a pharmaceutical
composition comprising a peptide, or a prodrug thereof, selected
from the group consisting of: (A) a dermorphin analog or a prodrug
thereof, wherein said dermorphin analog is a peptide of formula I
13wherein R.sup.1 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.7 branched or unbranched alkyl, phenyl,
hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl,
aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl,
cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,
mercaptobenzyl, and nitrobenzyl; R.sup.2 is hydrogen, methyl,
ethyl; or R.sup.1 and R.sup.2, taken together with the carbon atom
to which they are attached, form a cycloalkyl ring containing 3-5
carbon atoms; X is selected from the group consisting of C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; Y is selected from the
group C.dbd.O, N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and
Y, taken together, represent an olefin linkage wherein X and Y each
have a hydrogen atom attached thereto in a cis or trans
configuration; and n is 1-7; (B) an opioid peptide, or an analog
thereof, wherein said opioid peptide is a peptide of formula III
14wherein R.sup.1 is selected from (i) linear or branched
C.sub.1-C.sub.6 alkyl; (ii) C.sub.1-C.sub.6 alkoxy; R.sup.2 is
selected from (i) hydrogen; (ii) linear or branched C.sub.1-C.sub.6
alkyl; (iii) C.sub.1-C.sub.6 alkoxy; R.sup.3 and R.sup.4 is each
and independently selected from (i) hydrogen; (ii) linear or
branched C.sub.1-C.sub.6 alkyl; 15and R.sup.7, R.sup.8 and R.sup.9
is each independently selected from (i) hydrogen; (ii) halogen,
where "halogen" encompasses chloro, fluoro, bromo and iodo; and
(iii) linear or branched C.sub.1-C.sub.6 alkyl; and n is an integer
of from 1 to 5, (C)
H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2;
(D) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH.sub.2
wherein Xaa is L- or D-dimethylphenylalanine; (E) a deltorphin
analog or a prodrug thereof, wherein said deltorphin analog is a
peptide of formula V: Tyrosine-D-alanine-Xaa-Glutamic
Acid-Valine-Valine-Glycine-NH.sub.2 wherein Xaa is L-or
D-dimethylphenylalanine; (F) a compound which is an agonist or
partial agonist of vanilloid receptor VR1, including, but not
limited to, (i)
N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-[4-(m-
ethylsulfonylamino)benzyl]thiourea; and (ii)
N-(4-tert-butylbenzyl)-N'-[3--
methoxy-4-(methylsulfonylamino)benzyl]thiourea; (G) an enkephalin
peptide or a prodrug thereof, wherein said enkephalin peptide is a
peptide selected from the group represented by the formulae (i)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH; (ii)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH; (iii)
H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol; and
(iv) analogs thereof; and (H) a peptide linked to a
DMT-Tic-Pharmacophore having the structure
H-2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoqui-
noline-3-carboxylic acid, said peptide selected from the group
consisting of (i) H-DMT-Tic-Glycine-NH-Benzyl; and (ii)
H-DMT-Tic-NH--CH(CH.sub.2--C- OOH)-1-H-benzimidazole-2-yl.
46. A method for relieving pain, the method comprising orally
administering to a patient in need of pain relief an effective
pain-relieving amount of a pharmaceutical composition comprising a
peptide, or a prodrug thereof, wherein said peptide is selected
from the group consisting of: (A) a dermorphin analog or a prodrug
thereof, wherein said dermorphin analog is a peptide of formula I
16wherein R.sup.1 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.7 branched or unbranched alkyl, phenyl,
hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl,
aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl,
cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,
mercaptobenzyl, and nitrobenzyl; R.sup.2 is hydrogen, methyl,
ethyl; or R.sup.1 and R.sup.2, taken together with the carbon atom
to which they are attached, form a cycloalkyl ring containing 3-5
carbon atoms; X is selected from the group consisting of C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; Y is selected from the
group C.dbd.O, N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and
Y, taken together, represent an olefin linkage wherein X and Y each
have a hydrogen atom attached thereto in a cis or trans
configuration; and n is 1-7; (B) an opioid peptide, or an analog
thereof, wherein said opioid peptide is a peptide of formula III
17wherein R.sup.1 is selected from (i) linear or branched
C.sub.1-C.sub.6 alkyl; (ii) C.sub.1-C.sub.6 alkoxy; R.sup.2 is
selected from (i) hydrogen; (ii) linear or branched C.sub.1-C.sub.6
alkyl; (iii) C.sub.1-C.sub.6 alkoxy; R.sup.3 and R.sup.4 is each
and independently selected from (i) hydrogen; (ii) linear or
branched C.sub.1-C.sub.6 alkyl; 18and R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 is each independently selected from (i)
hydrogen; (ii) halogen, where "halogen" encompasses chloro, fluoro,
bromo and iodo; and (iii) linear or branched C.sub.1-C.sub.6 alkyl;
and n is an integer of from 1 to 5, (C)
H-2,6-dimethyltyrosine-D-Arginine-Phenylalani- ne-Lysine-NH.sub.2;
(D) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Se-
rine-NH.sub.2 wherein Xaa is L- or D-dimethylphenylalanine; (E) a
deltorphin analog or a prodrug thereof, wherein said deltorphin
analog is a peptide of formula V: Tyrosine-D-alanine-Xaa-Glutamic
Acid-Valine-Valine-Glycine-NH.sub.2 wherein Xaa is L-or
D-dimethylphenylalanine; (F) a compound which is an agonist or
partial agonist of vanilloid receptor VR1 including, but not
limited to, (i)
N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-[4-(methylsulfonylami-
no)benzyl]thiourea; and (ii)
N-(4-tert-butylbenzyl)-N'-[3-methoxy-4-(methy-
lsulfonylamino)benzyl]thiourea; (G) an enkephalin peptide or a
prodrug thereof, wherein said enkephalin peptide is a peptide
selected from the group represented by the formulae (i)
H-Tyrosine-Glycine-Glycine-Phenylal- anine-Methionine-OH;) (ii)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucin- e-OH; (iii)
H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-ol- ;
and (iii) (iv) analogs thereof; and (H) a peptide linked to a
DMT-Tic-Pharmacophore having the structure
H-2',6'-dimethyl-L-tyrosine-1,-
2,3,4-tetrahydroisoquinoline-3-carboxylic acid, said peptide
selected from the group consisting of (i)
H-DMT-Tic-Glycine-NH-Benzyl; and (ii)
H-DMT-Tic-NH--CH(CH.sub.2--COOH)-1-H-benzimidazole-2-yl.
47. The method of claim 46, wherein the pain is due to at least one
of labor and delivery
48. The method of claim 46, wherein said pain is due to
surgery.
49. A method for improving myocardial contractile force, the method
comprising orally administering to a patient in need of said
improvement an effective amount of a pharmaceutical composition
comprising a peptide, or a prodrug thereof, wherein said peptide is
selected from the group consisting of: (A) a dermorphin analog or a
prodrug thereof, wherein said dermorphin analog is a peptide of
formula I 19wherein R.sup.1 is selected from the group consisting
of hydrogen, C.sub.1-C.sub.7 branched or unbranched alkyl, phenyl,
hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl,
aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl,
cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,
mercaptobenzyl, and nitrobenzyl; R.sup.2 is hydrogen, methyl,
ethyl; or R.sup.1 and R.sup.2, taken together with the carbon atom
to which they are attached, form a cycloalkyl ring containing 3-5
carbon atoms; X is selected from the group consisting of C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; Y is selected from the
group C.dbd.O, N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and
Y, taken together, represent an olefin linkage wherein X and Y each
have a hydrogen atom attached thereto in a cis or trans
configuration; and n is 1-7; (B) an opioid peptide, or an analog
thereof, wherein said opioid peptide is a peptide of formula III
20wherein R.sup.1 is selected from (i) linear or branched
C.sub.1-C.sub.6 alkyl; (ii) C.sub.1-C.sub.6 alkoxy; R.sup.2 is
selected from (i) hydrogen; (ii) linear or branched C.sub.1-C.sub.6
alkyl; (iii) C.sub.1-C.sub.6 alkoxy; R.sup.3 and R.sup.4 is each
and independently selected from (i) hydrogen; (ii) linear or
branched C.sub.1-C.sub.6 alkyl; 21and R.sup.5, R.sup.6, R.sup.7,
R.sup.8 and R.sup.9 is each independently selected from (i)
hydrogen; (ii) halogen, where "halogen" encompasses chloro, fluoro,
bromo and iodo; and (iii) linear or branched C.sub.1-C.sub.6 alkyl;
and n is an integer of from 1 to 5; and (C)
Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Seri- ne-NH.sub.2
wherein Xaa is L- or D-dimethylphenylalanine.
50. A method for improving cardiac performance of a heart before,
during or after cardiac transplantation, the method comprising
orally administering to a patient in need of said improvement a
cardiac performance-improving effective amount of a pharmaceutical
composition comprising a peptide, or a prodrug thereof, wherein
said peptide is selected from the group consisting of: (A) a
dermorphin analog or a prodrug thereof, wherein said dermorphin
analog is a peptide of formula I 22wherein R.sup.1 is selected from
the group consisting of hydrogen, C.sub.1-C.sub.7 branched or
unbranched alkyl, phenyl, hydroxyphenyl, methoxyphenyl, benzyl,
hydroxybenzyl, methoxybenzyl, aminobenzyl, amidobenzyl,
carboxybenzyl, carboxymethylbenzyl, cyanobenzyl, fluorobenzyl,
chlorobenzyl, bromobenzyl, iodobenzyl, mercaptobenzyl, and
nitrobenzyl; R.sup.2 is hydrogen, methyl, ethyl; or R.sup.1 and
R.sup.2, taken together with the carbon atom to which they are
attached, form a cycloalkyl ring containing 3-5 carbon atoms; X is
selected from the group consisting of C.dbd.O, N--H, CH.sub.2,
--O--, C.dbd.S and --S--; Y is selected from the group C.dbd.O,
N--H, CH.sub.2, --O--, C.dbd.S and --S--; or X and Y, taken
together, represent an olefin linkage wherein X and Y each have a
hydrogen atom attached thereto in a cis or trans configuration; and
n is 1-7; (B) an opioid peptide, or an analog thereof, wherein said
opioid peptide is a peptide of formula III 23wherein R.sup.1 is
selected from (i) linear or branched C.sub.1-C.sub.6 alkyl; (ii)
C.sub.1-C.sub.6 alkoxy; R.sup.2 is selected from (i) hydrogen; (ii)
linear or branched C.sub.1-C.sub.6 alkyl; (iii) C.sub.1-C.sub.6
alkoxy; R.sup.3 and R.sup.4 is each and independently selected from
(i) hydrogen; (ii) linear or branched C.sub.1-C.sub.6 alkyl; 24and
R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is each
independently selected from (i) hydrogen; (ii) halogen, where
"halogen" encompasses chloro, fluoro, bromo and iodo; and (iii)
linear or branched C.sub.1-C.sub.6 alkyl; and n is an integer of
from 1 to 5; and (C) Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-P-
roline-Serine-NH.sub.2 wherein Xaa is L- or
D-dimethylphenylalanine.
Description
CROSS REFERENCE TO A RELATED APPLICATION
[0001] The present application is a 35 U.S.C. .sctn. 119 conversion
of Provisional Application Ser. No. 60/580,872 filed Jun. 18,
2004
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to oral peptide pharmaceutical
compositions having analgesic and/or cardiovascular activity, and
to methods of enhancing bioavailability of such peptides when
administered orally.
[0004] 2. Description of the Related Art
[0005] Opiates such as morphine and codeine, or opiate-like
synthetic drugs are currently used for the management of moderate
to severe pain. Many endogenous peptides of mammalian and amphibian
origin (e.g., the endorphins) also bind to opioid receptors and
elicit an analgesic response similar to classic narcotic opiates.
This led to the hope that these peptides might be produced
commercially and administered to patients to, e.g., relieve pain.
It was found, however, that side effects such as depression of
cardiac and respiratory function, tolerance, physical dependence
capacity and precipitated withdrawal syndrome are caused by
nonspecific interactions between such peptides and central nervous
system receptors. Such side effects are due to the interaction of
these peptides with multiple opioid receptors. For this reason,
peptides with a variety of structural modifications have been
developed in an effort to develop peptide-based pharmaceuticals
that are specific for a particular opioid receptor sub-type [mu,
delta and kappa], and which produce long-lasting antinociceptive
effects while minimizing undesirable side effects such as
depression of cardiac and/or respiratory function, extended
sedative activity, etc.
[0006] Peptide pharmaceuticals known in the prior art, including
the analgesic peptides described above, frequently have been
administered by injection or by nasal administration. A more
preferred oral administration tends to be problematic because
peptide-active compounds are very susceptible to degradation in the
stomach and intestines and show poor bioavailability. For example,
the prior art is not believed to have reported to achieve
reproducible blood levels of opioid peptides when administered
orally. This is believed to be because peptides lack sufficient
stability in the gastrointestinal tract, and tend to be poorly
transported through intestinal walls into the blood.
[0007] However, injection and nasal administration are
significantly less convenient, and involve more patient discomfort,
than oral administration. Often this inconvenience or discomfort
results in substantial patient noncompliance with a treatment
regimen. Thus there is a need in the art for a more effective and
reproducible oral administration of peptide pharmaceuticals
including, but not limited to, peptide pharmaceuticals having
analgesic and/or cardiovascular activity.
[0008] Proteolytic enzymes of both the stomach and intestines may
degrade peptides, rendering them inactive before they can be
absorbed into the bloodstream. Any amount of peptide that survives
proteolytic degradation by proteases of the stomach (typically
having acidic pH optima) is later confronted with proteases of the
small intestine and enzymes secreted by the pancreas (typically
having neutral to basic pH optima). Specific difficulties arising
from the oral administration of a peptide involve the relatively
large size of the molecule, and the charge distribution it carries.
This may make it more difficult for such peptides to penetrate the
mucus along intestinal walls or to cross the intestinal brush
border membrane into the blood. These additional problems may
further contribute to limited bioavailability.
SUMMARY OF THE INVENTION
[0009] Recent advances in the field of analgesic peptides have been
directed towards the derivatization of these peptides to protect
against enzymatic or hydrolytic degradation in order to increase
their half lives in circulation, and make them more selective for a
specific opioid receptor subclass to avoid deleterious and
potentially life-threatening side effects. However, even with such
stable and protease-resistant analogs, oral delivery is not
feasible due to low bioavailability.
[0010] It is accordingly an object of the present invention to
provide a therapeutically effective oral pharmaceutical composition
for reliably delivering pharmaceutical peptides, e.g.,
physiologically active peptide agents having analgesic and/or
cardiovascular activity.
[0011] It is a further object of the invention to provide
therapeutic methods for enhancing the bioavailability of such
peptides.
[0012] In one aspect, the invention provides a pharmaceutical
composition for the oral delivery of a peptide having analgesic
and/or cardiovascular activity. The composition comprises (A) a
therapeutically effective amount of an active peptide component (as
described below) and (B) at least one absorption enhancer effective
to promote bioavailability of the peptide or (C) at least one
pharmaceutically acceptable pH-lowering agent, wherein the
pH-lowering agent is present in the pharmaceutical composition in a
quantity which, if the composition were added to 10 milliliters of
0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of the solution to no higher than 5.5. In a further
embodiment (D), the pharmaceutical composition may include both the
absorption enhancer and the pH-lowering agent. In yet a further
embodiment (E), the pharmaceutical composition of (A), (B), (C) or
(D) may also include an acid-resistant protective vehicle effective
to transport the pharmaceutical composition through the stomach of
a patient while preventing contact between the active peptide
component and stomach proteases.
[0013] In another aspect, the invention is directed to a
pharmaceutical composition for the oral delivery of a peptide
having analgesic and/or cardiovascular activity, wherein the
composition comprises (A) a therapeutically effective amount of an
active peptide component (as described below) and (B) at least one
pharmaceutically acceptable pH-lowering agent, wherein the
pH-lowering agent is present in the pharmaceutical composition in a
quantity which, if the composition were added to 10 milliliters of
0.1M aqueous sodium bicarbonate solution, would be sufficient to
lower the pH of the solution to no higher than 5.5. The
pharmaceutical composition may optionally additionally comprise at
least one additional component selected from the group consisting
of (C) at least one absorption enhancer effective to promote
bioavailability of the peptide; and (D) an acid-resistant
protective vehicle effective to transport the pharmaceutical
composition through the stomach of a patient while preventing
contact between the active peptide component and stomach
proteases.
[0014] The active peptide component for inclusion in the
formulation of the invention is selected from among one or more of
the following: 1
[0015] wherein R.sup.1 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.7 branched or unbranched alkyl, phenyl,
hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl,
aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl,
cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,
mercaptobenzyl, and nitrobenzyl;
[0016] R.sup.2 is hydrogen, methyl, ethyl; or
[0017] R.sup.1 and R.sup.2, taken together with the carbon atom to
which they are attached, form a cycloalkyl ring containing 3-5
carbon atoms;
[0018] X is selected from the group consisting of C.dbd.O, N--H,
CH.sub.2, --O--, C.dbd.S and --S--;
[0019] Y is selected from the group C.dbd.O, N--H, CH.sub.2, --O--,
C.dbd.S and --S--; or
[0020] X and Y, taken together, represent an olefin linkage wherein
X and Y each have a hydrogen atom attached thereto in a cis or
trans configuration; and
[0021] n is 1-7;
[0022] (B) a peptide of formula II:
H-Tyrosine-A-Phenylalanine-B-NH.sub.2
[0023] wherein:
[0024] A is selected from the group consisting of D-.alpha.-amino
acids;
[0025] B is selected from the group consisting of .alpha.-amino
acids; and
[0026] the overall net positive charge of the peptide is +2 or
greater; 2
[0027] wherein
[0028] R.sup.1 is selected from
[0029] (i) linear or branched C.sub.1-C.sub.6 alkyl;
[0030] (ii) C.sub.1-C.sub.6 alkoxy;
[0031] R.sup.2 is selected from
[0032] (i) hydrogen;
[0033] (ii) linear or branched C.sub.1-C.sub.6 alkyl;
[0034] (iii) C.sub.1-C.sub.6 alkoxy;
[0035] R.sup.3 and R.sup.4 is each and independently selected
from
[0036] (i) hydrogen;
[0037] (ii) linear or branched C.sub.1-C.sub.6 alkyl; 3
[0038] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is each
independently selected from
[0039] (i) hydrogen;
[0040] (ii) halogen, where "halogen" encompasses chloro, fluoro,
bromo and iodo; and
[0041] (iii) linear or branched C.sub.1-C.sub.6 alkyl; and
[0042] n is an integer of from 1 to 5;
[0043] (D) A peptide of formula IV
Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH.sub.2
[0044] wherein Xaa is L- or D-dimethylphenylalanine;
[0045] (E) A peptide of formula V
Tyrosine-D-alanine-Xaa-Glutamic
Acid-Valine-Valine-Glycine-NH.sub.2
[0046] wherein Xaa is L-or D-dimethylphenylalanine;
[0047] (F) An enkephalin peptide; and
[0048] (G) A peptide linked to a DMT-Tic-pharmacophore.
[0049] In another aspect, the invention provides a pharmaceutical
composition for oral delivery of a compound having analgesic and/or
cardiovascular activity, wherein the composition comprises: (A) a
therapeutically effective amount of an active compound which is an
agonist or a partial agonist of vanilloid receptor VR1; and (B) at
least one absorption enhancer effective to promote bioavailability
of the compound or (C) at least one pharmaceutically acceptable
pH-lowering agent, wherein the pH-lowering agent is present in the
pharmaceutical composition in a quantity which, if the composition
were added to 10 milliliters of 0.1M aqueous sodium bicarbonate,
would be sufficient to lower the pH of the solution to no higher
than 5.5. In a further embodiment (D), the pharmaceutical
composition may include both the absorption enhancer and the
pH-lowering agent.
[0050] In yet another embodiment (E), the pharmaceutical
composition of (A), (B), (C) or (D) may also include an
acid-resistant protective vehicle effective to transport the
pharmaceutical composition through the stomach of a patient while
preventing contact between the active peptide component and stomach
proteases.
[0051] In a further aspect, any of the pharmaceutical compositions
of the invention may additionally comprise a water-soluble barrier
separating the pH-lowering agent from the protective vehicle.
[0052] In another aspect of the invention, any of the
pharmaceutical compositions may comprise granules containing a
pharmaceutical binder and, uniformly dispersed in the binder, at
least one of the pH-lowering agent, the absorption enhancer and the
peptide having analgesic and/or cardiovascular activity.
[0053] Additional aspects of the invention relate to therapeutic
methods involving oral administration of therapeutically effective
amounts of pharmaceutical compositions as described herein.
[0054] In one aspect, the invention provides a method for enhancing
the oral bioavailability of a compound comprising a peptide having
analgesic or cardiovascular activity. The method comprises orally
delivering a pharmaceutical composition that combines the compound
with at least one absorption enhancer effective to promote
bioavailability of the compound, or combining the compound with at
least one pH-lowering agent, wherein the pH-lowering agent is
present in a quantity which, if the composition were added to 10
milliliters of 0.1 M aqueous sodium bicarbonate solution, would be
sufficient to lower the pH of the solution to no higher than 5.5.
The method may also comprise orally delivering a pharmaceutical
composition that combines the compound with at least one absorption
enhancer in combination with at least one pH-lowering agent. The
method may also comprise transporting any of the above
pharmaceutical compositions through the stomach of a patient by an
acid-resistant protective vehicle to prevent contact between the
pharmaceutical composition and stomach proteases.
[0055] In another aspect, the invention provides a method for
stimulating a mu, delta or kappa-opioid receptor in a mammal in
need of such stimulation, wherein the method comprises orally
administering to the mammal an effective opioid receptor
stimulating amount of one or more of the pharmaceutical
compositions described herein.
[0056] In an additional aspect, the invention provides a method for
relieving pain comprising orally administering to a patient in need
of pain relief an effective pain-relieving amount of one or more of
the pharmaceutical compositions described herein.
[0057] In a further aspect, the invention provides a method for
improving myocardial contractile force. The method comprises orally
administering to a patient in need of such improvement an effective
contractile force-increasing amount of one or more of the
pharmaceutical compositions described herein containing a
therapeutically effective amount of a dermorphin analog or a
prodrug thereof.
[0058] In another aspect, the invention provides a method for
improving cardiac performance of a heart before, during and/or
after cardiac transplantation. The method comprises orally
administering to a patient in need of such improved cardiac
performance an effective cardiac performance-improving amount of
one or more of the pharmaceutical compositions described herein
containing a therapeutically effective amount of a dermorphin
analog or a prodrug thereof.
[0059] In the context of the invention, prodrugs of any of the
above-described active peptides useful in forming the compositions
of the invention may be used in place of the corresponding peptide,
as these will also increase the serum levels of the peptide. The
prodrug is converted in vivo to the desired active compound by a
well-known mechanism. The pharmaceutical industry frequently uses
salt or ester prodrugs to deliver a large number of pharmaceutical
agents. It is, in fact, rare in the pharmaceutical industry that
particular active ingredients that are to be delivered to the
bloodstream of a patient are not formulated (in their dosage form)
as a prodrug which, as noted above, is subsequently converted in
vivo to the desired active compound by such well-known mechanism.
The term "prodrug" as used herein is meant to include only those
compounds which, when converted in vivo, deliver one or more of the
active peptides described and claimed herein to the bloodstream of
a subject to whom they are administered. A variety of well-known
prodrug forms of various functional groups that may appear on the
active peptide compounds for use in the invention are set forth in
A Textbook of Drug Design and Development, Bundgaard and
Krosgaard-Larsen, Ed., (Harwook Academic Publishers GmfH, Chur,
Switzerland) 1991 which is incorporated herein by reference.
[0060] Other features and advantages of the present invention will
become apparent from the following detailed description of the
invention.
BRIEF DESCRIPTION OF THE FIGURES
[0061] FIG. 1 provides, in graphical form, pharmacokinetic profiles
following administration of unformulated Dmt-DALDA and Dmt-DALDA
formulated with an absorption enhancer and pH-lowering agent by
duodenal injection in anesthetized rats.
[0062] FIG. 2 provides, in graphical form, pharmacokinetic profiles
following administration to beagle dogs of salmon calcitonin (sCT)
plus Dmt-DALDA with citric acid and lauroyl carnitine, in a solid
dosage capsule formulation, either without (FIG. 2A) or with (FIG.
2B) an enteric coating.
DETAILED DESCRIPTION OF THE INVENTION
[0063] In accordance with the invention, patients in need of
treatment with peptides having analgesic and/or cardiovascular
activity are provided with an oral pharmaceutical composition
thereof (at appropriate dosage), preferably but not necessarily in
tablet or capsule form of an ordinary size in the pharmaceutical
industry. The dosages and frequency of administering the products
are discussed in more detail below. Patients who may benefit are
any who suffer from disorders that respond favorably to increased
levels of a peptide-containing compound. For example, oral
administration of dermorphin, deltorphin and/or enkephalin peptide
analogs in accordance with the invention may be used to treat
patients in need of pain relief, or those with conditions
warranting improved cardiac performance, e.g., by improving
myocardial contractile force.
[0064] Without intending to be bound by theory, the pharmaceutical
compositions of the invention are believed to overcome a series of
different and unrelated natural barriers to bioavailability.
Various components of the pharmaceutical compositions act to
overcome different barriers by mechanisms appropriate to each, and
result in synergistic effects on the bioavailability of a peptide
active ingredient.
[0065] The peptide active compound may be administered orally. In
accordance with the invention, proteolytic degradation of the
peptide by stomach proteases (most of which are active in the acid
pH range) and intestinal or pancreatic proteases (most of which are
active in the neutral to basic pH range) is reduced. Solubility
enhancers aid passage of the peptide active agent through the
intestinal epithelial barrier.
[0066] Again, without intending to be bound by theory, it appears
that, in accordance with one embodiment of the present invention,
the peptide is transported through the stomach under the protection
of an appropriate acid-resistant protective vehicle for
substantially preventing contact between the active peptide and any
stomach proteases capable of degrading it. Once the pharmaceutical
composition of the invention passes through the stomach and enters
the intestinal region where basic to neutral pH predominates, and
where proteases tend to have basic to neutral pH optima, the
enteric coating or other vehicle releases the peptide and acid (in
close proximity to each other).
[0067] The pH-lowering agent is believed to lower the local
intestinal pH (where the active agent has been released) to levels
below the optimal range for many intestinal proteases. This
decrease in pH reduces the proteolytic activity of the intestinal
proteases, thus affording protection to the peptide from potential
degradation. The activity of these proteases is diminished by the
temporarily acidic local environment provided by the invention. It
is preferred that sufficient acid be provided that local intestinal
pH is lowered temporarily to 5.5 or below, preferably 4.7 or below
and more preferably 3.5 or below. The sodium bicarbonate test
described below (in the section below captioned "the pH-Lowering
Agent") is indicative of the required acid amount. Preferably,
conditions of reduced intestinal pH persist for a time period
sufficient to protect the peptide agent from proteolytic
degradation until at least some of the peptide agent has had an
opportunity to cross the intestinal wall into the bloodstream. The
absorption enhancers of the invention synergistically promote
peptide absorption into the blood while conditions of reduced
proteolytic activity prevail.
[0068] The mechanism by which the invention is believed to
accomplish the goal of enhanced bioavailability is aided by having
active components of the pharmaceutical composition released
together as simultaneously as possible. To this end, it is
preferred to keep the volume of enteric coating as low as possible
consistent with providing protection from stomach proteases. Thus
enteric coating is less likely to interfere with peptide release,
or with the release of other components in close time proximity
with the peptide. The enteric coating should normally add less than
30% to the weight of the remainder of pharmaceutical composition
(i.e., the other components of the composition excluding enteric
coating). Preferably, it is less than 20% and, more preferably, the
enteric coating adds between 10% and 20% to the weight of the
uncoated ingredients.
[0069] The absorption enhancer which may be a solubility enhancer
and/or transport enhancer (as described in more detail below) aids
transport of the peptide agent from the intestine to the blood, and
may promote the process so that it better occurs during the time
period of reduced intestinal pH and reduced intestinal proteolytic
activity. Many surface active agents may act as both solubility
enhancers and transport (uptake) enhancers. Again without intending
to be bound by theory, it is believed that enhancing solubility
provides (1) a more simultaneous release of the active components
of the invention into the aqueous portion of the intestine, (2)
better solubility of the peptide in, and transport through, a
mucous layer along the intestinal walls. Once the peptide active
ingredient reaches the intestinal walls, an uptake enhancer
provides better transport through the brush border membrane of the
intestine into the blood, via either transcellular or paracellular
transport. As discussed in more detail below, many preferred
compounds may provide both functions. In those instances, preferred
embodiments utilizing both of these functions may do so by adding
only one additional compound to the pharmaceutical composition. In
other embodiments, separate absorption enhancers may provide the
two functions separately.
[0070] Each of the preferred ingredients of the pharmaceutical
composition of the invention is separately discussed below.
Combinations of multiple pH-lowering agents, or multiple enhancers
can be used as well as using just a single pH-lowering agent and/or
single enhancer. Some preferred combinations are also discussed
below.
[0071] In one embodiment of the present invention, the
pharmaceutical composition for oral delivery may comprise the
peptide or compound in combination with an absorption enhancer and
a pH-lowering agent, along with an enteric coating to transport the
ingredients through the stomach of a patient while preventing
contact between the pharmaceutical composition and stomach
proteases.
[0072] In another embodiment, it has been shown from experiments
with several peptides that a pharmaceutical composition for oral
delivery that comprises only a peptide with a pH-lowering agent
provides a significant increase in bioavailability compared to that
offered by the peptide taken alone.
[0073] In yet another embodiment, it has been shown from
experimentation with a variety of peptides that a pharmaceutical
composition for oral delivery comprising only a peptide and an
absorption enhancer provides a significant increase in
bioavailability, compared to that of the peptide taken alone.
[0074] Peptide Active Ingredients
[0075] Peptide active ingredients which may benefit from oral
delivery in accordance with the invention include peptides having
analgesic or cardiovascular activity. Several non-limiting examples
of such peptides are described below, however, as one of ordinary
skill in this art would recognize, various additional peptides,
analogs and/or prodrugs may be substituted for the peptides
described herein in the formulations prepared according to the
invention.
[0076] In a first embodiment, a peptide for use with the invention
may be a dermorphin analog, or a prodrug thereof, of formula I
4
[0077] wherein R.sup.1 is selected from the group consisting of
hydrogen, C.sub.1-C.sub.7 branched or unbranched alkyl, phenyl,
hydroxyphenyl, methoxyphenyl, benzyl, hydroxybenzyl, methoxybenzyl,
aminobenzyl, amidobenzyl, carboxybenzyl, carboxymethylbenzyl,
cyanobenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,
mercaptobenzyl, and nitrobenzyl;
[0078] R.sup.2 is hydrogen, methyl, ethyl; or
[0079] R.sup.1 and R.sup.2, taken together with the carbon atom to
which they are attached, form a cycloalkyl ring containing 3-5
carbon atoms;
[0080] X is selected from the group consisting of C.dbd.O, N--H,
CH.sub.2, --O--, C.dbd.S and --S--;
[0081] Y is selected from the group C.dbd.O, N--H, CH.sub.2, --O--,
C.dbd.S and --S--; or X and Y, taken together, represent an olefin
linkage wherein X and Y each have a hydrogen atom attached thereto
in a cis or trans configuration; and
[0082] n is 1-7.
[0083] Useful dermorphin analogs falling within the scope of
formula I include, but are not limited to:
[0084] (A)
H-Tyrosine-D-Norvaline-Phenylalanine-Ornithine-NH.sub.2;
[0085] (B)
H-Tyrosine-D-Norleucine-Phenylalanine-Ornithine-NH.sub.2;
[0086] (C)
H-Tyrosine-D-Arginine-Phenylalanine-.alpha.,.gamma.-diaminobuty-
ric acid-NH.sub.2;
[0087] (D) H-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2;
[0088] (E)
H-Lysine-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2; and
[0089] (F)
N'-amidino-Tyrosine-D-arginine-Phenylalanine-Methyl-.alpha.-ala-
nine-OH.
[0090] In a preferred embodiment, the peptide of the invention is
H-Tyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2 ("DALDA").
[0091] In another embodiment, the peptide for use with the
invention may be a dermorphin analog of formula II, or a prodrug
thereof:
H-Tyrosine-A-Phenylalanine-B-NH.sub.2
[0092] wherein:
[0093] A is selected from the group consisting of D-.alpha.-amino
acids;
[0094] B is selected from the group consisting of .alpha.-amino
acids; and
[0095] the overall net positive charge of the peptide is +2 or
greater
[0096] D-.alpha.-amino acids useful in forming the compositions of
the invention include, but are not limited to, D-norvaline,
D-norleucine, D-arginine, D-alanine, D-valine, D-isoleucine,
D-leucine, D-serine, D-phenylalanine and
D-.alpha.,.gamma.-diaminobutyric acid. Alpha-amino acids useful in
forming the compositions of the invention include, but are not
limited to phenylalanine, para-fluoro phenylalanine, ornithine,
.alpha.,.gamma.-diaminobutyric acid, lysine, norvaline, arginine,
.alpha.,.beta.-diaminopropionic acid and homolysine. In a preferred
embodiment, the overall net positive charge of the peptide may be
+2 or +3.
[0097] In a further embodiment, the peptide may be a DALDA
derivative of formula III: 5
[0098] wherein
[0099] R.sup.1 is selected from
[0100] (i) linear or branched C.sub.1-C.sub.6 alkyl;
[0101] (ii) C.sub.1-C.sub.6 alkoxy;
[0102] R.sup.2 is selected from
[0103] (i) hydrogen;
[0104] (ii) linear or branched C.sub.1-C.sub.6 alkyl;
[0105] (iii) C.sub.1-C.sub.6 alkoxy;
[0106] R.sup.3 and R.sup.4 is each and independently selected
from
[0107] (i) hydrogen;
[0108] (ii) linear or branched C.sub.1-C.sub.6 alkyl; 6
[0109] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is each
independently selected from
[0110] (i) hydrogen;
[0111] (ii) halogen, where "halogen" encompasses chloro, fluoro,
bromo and iodo; and
[0112] (iii) linear or branched C.sub.1-C.sub.6 alkyl; and
[0113] n is an integer of from 1 to 5.
[0114] More particularly, in one embodiment of the above-described
peptide,
[0115] R.sup.1 is a linear C.sub.1-C.sub.6 alkyl;
[0116] R.sup.2 is a linear C.sub.1-C.sub.6 alkyl or hydrogen;
[0117] R.sup.3 and R.sup.4 is each and independently selected from
a straight C.sub.1-C.sub.6 alkyl or hydrogen;
[0118] R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 is each and
independently selected from
[0119] (i) hydrogen;
[0120] (ii) a halogen selected from chloro, fluoro, bromo and iodo;
and
[0121] (iii) linear or branched C.sub.1-C.sub.6 alkyl, and
[0122] n is an integer from 1 to 5.
[0123] In an alternate version of the subject embodiment,
[0124] R.sup.1 is CH.sub.3;
[0125] R.sup.2 is hydrogen or CH.sub.3;
[0126] R.sup.3 and R.sup.4 are both hydrogen;
[0127] R.sup.5, R.sup.6, R.sup.7, R.sup.1 and R.sup.9 are all
hydrogen; and
[0128] n=4.
[0129] In a preferred embodiment, the dermorphin analog is a
peptide represented by the formula:
H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2.
("DMT-DALDA")
[0130] In an additional embodiment of the invention, the peptide is
a dermorphin analog of formula IV:
Tyrosine-D-alanine-Xaa-Glycine-Tyrosine-Proline-Serine-NH.sub.2
[0131] wherein Xaa is L- or D-dimethylphenylalanine.
[0132] In a further embodiment of the invention, the peptide for
use with the invention is a deltorphin analog of formula V:
Tyrosine-D-alanine-Xaa-Glutamic
Acid-Valine-Valine-Glycine-NH.sub.2
[0133] wherein Xaa is L-or D-dimethylphenylalanine.
[0134] An alternate embodiment of the invention involves the
inclusion of compounds having analgesic and/or cardiovascular
activity which, although not peptides, display characteristics
which are similar thereto and which are subject to many of the same
considerations with regard to transport and adsorption as the
peptides described herein. These compounds are agonists or partial
agonists of the vanilloid receptor VR1. Examples of these compounds
include, but are not limited to:
[0135] (i)
N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N'-[4-(methyls-
ulfonylamino)benzyl]thiourea; and
[0136] (ii)
N-(4-tert-butylbenzyl)-N'-[3-methoxy-4-(methylsulfonylamino)be-
nzyl]thiourea.
[0137] In an additional embodiment of the invention, the peptide is
an enkephalin peptide, or a prodrug thereof. Examples of such
enkephalin peptides include, but are not limited to:
[0138] (i) H-Tyrosine-Glycine-Glycine-Phenylalanine-Methionine-OH;
(i)
[0139] (ii)
H-Tyrosine-Glycine-Glycine-Phenylalanine-Leucine-OH;
[0140] (iii)
H-Tyrosine-D-alanine-Glycine-N-methyl-phenylalanine-Glycine-o- l;
and
[0141] (iv) analogs thereof.
[0142] In still another embodiment, the peptide may be linked to a
DMT-Tic-Pharmacaphore having the structure
[0143]
H-2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carbox-
ylic acid.
[0144] Peptides for use in the invention include, but are not
limited to those selected from the group consisting of
[0145] (i) H-DMT-Tic-Glycine-NH-Benzyl; and
[0146] (ii)
H-DMT-Tic-NH-CH(CH.sub.2--COOH)--1-H-benzimidazole-2-yl.
[0147] The peptides having analgesic and/or cardiovascular activity
for use in the invention may be prepared in accordance with
Examples 2 and 3 of U.S. Pat. No. 5,602,100 to Brown et al., which
is incorporated herein by reference. Example 2 of the subject
patent teaches the method of peptide synthesis. Peptides containing
c-terminal free acids can be synthesized by linking BOC amino acids
using a chloro methyl resin [Merrifield resin], 1% cross linked,
100-200 mesh obtained from Peptides International [Lousiville,
Ky.]. Example 3 describes methodology for use in purifying the
resultant peptides. In particular, a preferred peptide for use in
the invention, i.e., Dmt-DALDA, may be prepared as shown in Example
1 of U.S. Pat. No. 6,703,483 to Schiller, which is also
incorporated by reference.
[0148] Compounds having analgesic and/or cardiovascular activity
which are useful in the invention further include agonists or
partial agonists of vanilloid receptor VR1. Methods for preparing
these compounds are set forth in, for example, International Patent
Publications WO 02/16318 and WO 02/16319 of Suh, et al., both dated
Feb. 28, 2002. Both of these publications are incorporated herein
by reference.
[0149] The pH-Lowering Agent
[0150] The total amount of the pH-lowering agent to be administered
with each administration of the pharmaceutical composition should
preferably be an amount which, when it is released into the
intestine, is sufficient to lower the local intestinal pH
substantially below the pH optima for proteases found there. The
quantity required will necessarily vary with several factors
including the type of pH-lowering agent used (discussed below) and
the equivalents of protons provided by a given pH-lowering agent.
In practice, the amount required to provide good bioavailability is
an amount which, when added to a solution of 10 milliliters of 0.1
M sodium bicarbonate, lowers the pH of that sodium bicarbonate
solution to no higher than 5.5, and preferably no higher than 4.7,
most preferably no higher than 3.5. Enough acid to lower pH, in the
foregoing test, to about 2.8 may been used in some embodiments.
Preferably at least 300 milligrams, and more preferably at least
400 milligrams of the pH-lowering agent are used in the
pharmaceutical composition of the invention. The foregoing
preferences relate to the total combined weight of all pH-lowering
agents where two or more of such agents are used in combination.
The oral formulation should not include an amount of any base
which, when released together with the pH-lowering compound, would
prevent the pH of the above-described sodium bicarbonate test from
dropping to 5.5 or below.
[0151] The pH-lowering agent of the invention may be any
pharmaceutically acceptable compound that is not toxic in the
gastrointestinal tract and is capable of either delivering hydrogen
ions (a traditional acid) or of inducing higher hydrogen ion
content from the local environment. It may also be any combination
of such compounds. It is preferred that at least one pH-lowering
agent used in the invention have a pKa no higher than 4.2, and
preferably no higher than 3.0. It is also preferred that the pH
lowering agent have a solubility in water of at least 30 grams per
100 milliliters of water at room temperature.
[0152] Examples of compounds that induce higher hydrogen ion
content include aluminum chloride and zinc chloride.
Pharmaceutically acceptable traditional acids include, but are not
limited to acid salts of amino acids (e.g. amino acid
hydrochlorides) or derivatives thereof. Examples of these are acid
salts of acetylglutamic acid, alanine, arginine, asparagine,
aspartic acid, betaine, carnitine, camosine, citrulline, creatine,
glutamic acid, glycine, histidine, hydroxylysine, hydroxyproline,
hypotaurine, isoleucine, leucine, lysine, methylhistidine,
norleucine, ornithine, phenylalanine, proline, sarcosine, serine,
taurine, threonine, tryptophan, tyrosine and valine.
[0153] Other examples of useful pH-lowering compounds include
carboxylic acids such as acetylsalicylic, acetic, ascorbic, citric,
fumaric, glucuronic, glutaric, glyceric, glycocolic, glyoxylic,
isocitric, isovaleric, lactic, maleic, oxaloacetic, oxalosuccinic,
propionic, pyruvic, succinic, tartaric, valeric, and the like.
[0154] Other useful pH-lowering agents that might not usually be
called "acids" in the art, but which may nonetheless be useful in
accordance with the invention are phosphate esters (e.g., fructose
1,6 diphosphate, glucose 1,6 diphosphate, phosphoglyceric acid, and
diphosphoglyceric acid).
[0155] CARBOPOL..RTM.. (Trademark BF Goodrich) and polymers such as
polycarbophil may also be used to lower pH.
[0156] Any combination of pH lowering agent that achieves the
required pH level of no higher than 5.5 in the sodium bicarbonate
test discussed above may be used. One preferred embodiment
utilizes, as at least one of the pH-lowering agents of the
pharmaceutical composition, an acid selected from the group
consisting of citric acid, tartaric acid and an acid salt of an
amino acid.
[0157] When DMT-DALDA is the peptide active agent, certain ratios
of pH-lowering agent to DMT-DALDA have proven especially effective.
It is preferred that the weight ratio of pH-lowering agent to
DMT-DALDA exceed 40: 1, preferably 400:1 and most preferably
4000:1.
[0158] The Absorption Enhancer
[0159] The absorption enhancers are preferably present in a
quantity that constitutes from 0.1 to 20.0 percent by weight,
relative to the overall weight of the pharmaceutical composition
(exclusive of the enteric coating). Preferred absorption enhancers
are surface active agents which act both as solubility enhancers
and uptake enhancers. Generically speaking, "solubility enhancers"
improve the ability of the components of the invention to be
solubilized in either the aqueous environment into which they are
originally released or into the lipophilic environment of the
mucous layer lining the intestinal walls, or both. "Transport
(uptake) enhancers" (which are frequently the same surface active
agents used as solubility enhancers) are those which facilitate the
ease by which peptide agents cross the intestinal wall.
[0160] One or more absorption enhancers may perform one function
only (e.g., solubility), or one or more absorption enhancers may
perform the other function only (e.g., uptake), within the scope of
the invention. It is also possible to have a mixture of several
compounds some of which provide improved solubility, some of which
provide improved uptake and/or some of which perform both.
[0161] Without intending to be bound by theory, it is believed that
uptake enhancers may act by (1) increasing disorder of the
hydrophobic region of the membrane exterior of intestinal cells,
allowing for increased transcellular transport; or (2) leaching
membrane proteins resulting in increased transcellular transport;
or (3) widening pore radius between cells for increased
paracellular transport.
[0162] Surface active agents are believed to be useful both as
solubility enhancers and as uptake enhancers.
[0163] For example, detergents are useful in (1) solubilizing all
of the active components quickly into the aqueous environment where
they are originally released, (2) enhancing lipophilicity of the
components of the invention, especially the peptide active agent,
aiding its passage into and through the intestinal mucus, (3)
enhancing the ability of the normally polar peptide active agent to
cross the epithelial barrier of the brush border membrane; and (4)
increasing transcellular or paracellular transport as described
above.
[0164] When surface active agents are used as the absorption
enhancers, it is preferred that they be free flowing powders for
facilitating the mixing and loading of capsules during the
manufacturing process. Because of inherent characteristics of
certain peptides (e.g., their isoelectric point, molecular weight,
amino acid composition, etc.) certain surface active agents
interact best with certain peptides.
[0165] Indeed, some can undesirably interact with the charged
portions of certain peptides and thus prevent their absorption,
thus undesirably resulting in decreased bioavailability. It is
preferred, when trying to increase the bioavailability of peptides
that any surface active agent used as an absorption enhancer be
selected from the group consisting of (i) anionic surface active
agents that are cholesterol derivatives (e.g., bile acids), (ii)
cationic surface agents (e.g., acyl carnitines, phospholipids and
the like), (iii) non-ionic surface active agents, and (iv) mixtures
of anionic surface active agents (especially those having linear
hydrocarbon regions) together with negative charge
neutralizers.
[0166] Negative charge neutralizers include but are not limited to
acyl carnitines, cetyl pyridinium chloride, and the like. Acyl
carnitines (e.g., lauroyl carnitine) are particularly good
absorption enhancers.
[0167] It is also preferred that the absorption enhancer be soluble
at acid pH, particularly in the 3.0 to 5.0 range.
[0168] To reduce the likelihood of side effects, preferred
detergents, when used as the absorption enhancers of the invention,
are either biodegradable or reabsorbable (e.g. biologically
recyclable compounds such as bile acids, phospholipids, and/or acyl
camitines), preferably biodegradable.
[0169] Acylcarnitines are believed particularly useful in enhancing
paracellular transport.
[0170] Absorption enhancers may also include: (a) salicylates such
as sodium salicylate, 3-methoxysalicylate, 5-methoxysalicylate and
homovanilate; (b) bile acids such as taurocholic,
tauorodeoxycholic, deoxycholic, cholic, glycholic, lithocholate,
chenodeoxycholic, ursodeoxycholic, ursocholic, dehydrocholic,
fusidic, etc.; (c) non-ionic surfactants such as polyoxyethylene
ethers (e.g. Brij 36T, Brij 52, Brij 56, Brij 76, Brij 96, Texaphor
A6, Texaphor A14, Texaphor A60 etc.), p-t-octyl phenol
polyoxyethylenes (Triton X-45, Triton X-100, Triton X-114, Triton
X-305 etc.) nonylphenoxypoloxyethylenes (e.g. Igepal CO series),
polyoxyethylene sorbitan esters (e.g. Tween-20, Tween-80 etc.); (d)
anionic surfactants such as dioctyl sodium sulfosuccinate; (e)
lyso-phospholipids such as lysolecithin and
lysophosphatidylethanolamine; (f) acylcarnitines, acylcholines and
acyl amino acids such as lauroylcarnitine, myristoylcarnitine,
palmitoylcarnitine, lauroylcholine, myristoylcholine,
palmitoylcholine, hexadecyllysine, N-acylphenylalanine,
N-acylglycine etc.; g) water soluble phospholipids such as
diheptanoylphosphatidylcholine, dioctylphosphatidylcholine
etc.;
[0171] (h) medium-chain glycerides which are mixtures of mono-, di-
and triglycerides containing medium-chain-length fatty acids
(caprylic, capric and lauric acids); (i)
ethylene-diaminetetraacetic acid; (j) cationic surfactants such as
cetylpyridinium chloride; (k) fatty acid derivatives of
polyethylene glycol such as Labrasol, Labrafac, etc.; and (1)
alkylsaccharides such as lauryl maltoside, lauroyl sucrose,
myristoyl sucrose, palmitoyl sucrose, etc.
[0172] In some preferred embodiments, and without intending to be
bound by theory, cationic ion exchange agents (e.g. detergents) are
included to provide solubility enhancement by another possible
mechanism. In particular, they may prevent the binding of the
peptide active agents to mucus.
[0173] Preferred cationic ion exchange agents include protamine
chloride or any other polycation.
[0174] Other Optional Ingredients
[0175] It is preferred that a water-soluble barrier separate the
pH-lowering agent from the acid resistant protective vehicle. A
conventional pharmaceutical capsule may, for example, be used for
the purpose of providing this barrier. Many water soluble barriers
are known in the art and include, but are not limited to,
hydroxypropyl methylcellulose and conventional pharmaceutical
gelatins.
[0176] In some preferred embodiments, another peptide (such as
albumin, casein, soy protein, other animal or vegetable proteins
and the like) is included to reduce non-specific adsorption (e.g.,
binding of peptide to the intestinal mucus barrier) thereby
lowering the necessary concentration of the expensive peptide
active agent. When added, the peptide is preferably from 1.0 to
10.0 percent by weight relative to the weight of the overall
pharmaceutical composition (excluding protective vehicle).
Preferably, this second peptide is not physiologically active and
is most preferably a food peptide such as soy bean peptide or the
like. Without intending to be bound by theory, this second peptide
may also increase bioavailability by acting as a protease scavenger
that desirably competes with the peptide active agent for protease
interaction. The second peptide may also aid the active compound's
passage through the liver.
[0177] All pharmaceutical compositions of the invention may
optionally also include common pharmaceutical diluents, glycants,
lubricants, gelatin capsules, preservatives, colorants and the like
in their usual known sizes and amounts.
[0178] The Protective Vehicle
[0179] Any carrier or vehicle that protects the peptide active
agent from stomach proteases and then dissolves so that the other
ingredients of the invention may be released in the intestine is
suitable.
[0180] Many such enteric coatings are known in the art, and are
useful in accordance with the invention.
[0181] Examples include cellulose acetate phthalate, hydroxypropyl
methylethylcellulose succinate, hydroxypropyl methylcellulose
phthalate, carboxylmethylethylcellulose and methacrylic acid-methyl
methacrylate copolymer. In some embodiments, the active peptide,
absorption enhancers such as solubility and/or uptake enhancer(s),
and pH-lowering compound(s), are included in a sufficiently viscous
protective syrup to permit protected passage of the components of
the invention through the stomach.
[0182] Suitable enteric coatings for protecting the peptide agent
from stomach proteases may be applied, for example, to capsules
after the remaining components of the invention have been loaded
within the capsule. In other embodiments, enteric coating is coated
on the outside of a tablet or coated on the outer surface of
particles of active components which are then pressed into tablet
form, or loaded into a capsule, which is itself preferably coated
with an enteric coating.
[0183] It is very desirable that all components of the invention be
released from the carrier or vehicle, and solubilized in the
intestinal environment as simultaneously as possible. It is
preferred that the vehicle or carrier release the active components
in the small intestine where uptake enhancers that increase
transcellular or paracellular transport are less likely to cause
undesirable side effects than if the same uptake enhancers were
later released in the colon. It is emphasized, however, that the
present invention is believed effective in the colon as well as in
the small intestine. Numerous vehicles or carriers, in addition to
the ones discussed above, are known in the art. It is desirable
(especially in optimizing how simultaneously the components of the
invention are released) to keep the amount of enteric coating low.
Preferably, the enteric coating adds no more than 30% to the weight
of the remainder of pharmaceutical composition (the "remainder"
being the pharmaceutical composition exclusive of enteric coating
itself). More preferably, it adds less than 20%, especially from
12% to 20% to the weight of the uncoated composition. The enteric
coating preferably should be sufficient to prevent breakdown of the
pharmaceutical composition of the invention in 0. 1N HCl for at
least two hours, then capable of permitting complete release of all
contents of the pharmaceutical composition within thirty minutes
after pH is increased to 6.3 in a dissolution bath in which said
composition is rotating at 100 revolutions per minute.
[0184] Other Preferences
[0185] It is preferred that the weight ratio of pH-lowering
agent(s) to absorption enhancer(s) be between 3:1 and 20: 1,
preferably 4:1-12:1, and most preferably 5:1-10:1. The total weight
of all pH-lowering agents and the total weight of all absorption
enhancers in a given pharmaceutical composition is included in the
foregoing preferred ratios. For example, if a pharmaceutical
composition includes two pH-lowering agents and three absorption
enhancers, the foregoing ratios will be computed on the total
combined weight of both pH-lowering agents and the total combined
weight of all three absorption enhancers.
[0186] It is preferred that the pH-lowering agent, the peptide
active agent and the absorption enhancer (whether single compounds
or a plurality of compounds in each category) be uniformly
dispersed in the pharmaceutical composition. In one embodiment, the
pharmaceutical composition comprises granules that include a
pharmaceutical binder having the peptide active agent, the
pH-lowering agent and the absorption enhancer uniformly dispersed
within said binder. Preferred granules may also consist of an acid
core, surrounded by a uniform layer of organic acid, a layer of
enhancer and a layer of peptide that is surrounded by an outer
layer of organic acid. Granules may be prepared from an aqueous
mixture consisting ofpharmaceutical binders such as polyvinyl
pyrrolidone or hydroxypropyl methylcellulose, together with the
pH-lowering agents, absorption enhancers and peptide active agents
of the invention.
[0187] Manufacturing Process
[0188] A preferred pharmaceutical composition of the invention
includes a size OO gelatin or HPMC (hydroxypropylmethyl cellulose)
capsule filled with 0.25 mg of the active peptide component with
analgesic and/or cardiovascular activity, 400 mg of granular citric
acid (available for example from Archer Daniels Midland Corp.) and
50 mg lauroyl carnitine (SIGMA)
[0189] All of the ingredients are preferably for eventual insertion
into the gelatin or HPMC capsule, and are preferably powders which
may be added to a blender in any order. Thereafter, the blender is
run for about five minutes until the powders are thoroughly
intermixed. Then the mixed powders are loaded into the large end of
the gelatine capsules. The other end of the capsule is then added,
and the capsule snapped shut. 500 or more such capsules may be
added to a coating device (e.g., Vector LDCS 20/30 Laboratory
Development Coating System (available from Vector Corp., Marion,
Iowa)).
[0190] An enteric coating solution is made as follows. Weigh 500
grams of EUDRAGIT L30 D-55 (a methacrylic acid copolymer with
methacylic acid methyl ester, an enteric coating available from
ROHM Pharma Polymers Inc., Maidan, Mass.). Add 411 grams distilled
water, 15 grams triethyl citrate and 38 grams talc. This amount of
coating will be sufficient to coat about 500 size OO capsules.
[0191] The capsules are weighed and placed into the drum of the
coating machine. The machine is turned on to rotate the drum (now
containing capsules) at 24-28 rpm. The temperature of inlet sprayer
is preferably about 45 .degree. C. Exhaust temperatures are
preferably about 30 .degree. C. Uncoated capsule temperature is
preferably about 25 .degree. C. Air flow is about 38 cubic feet per
minute.
[0192] A tube from the machine is then inserted into the coating
solution prepared as discussed above. The pump is then turned on
for feeding solution into the coating device. Coating then proceeds
automatically. The machine can be stopped at any time to weigh
capsules to determine if the coating amount is sufficient. Usually
coating is allowed to proceed for 60 minutes. The pump is then
turned off for about five minutes while the machine is still
running to help dry the coated capsules. The machine can then be
turned off. The capsule coating is then complete, although it is
recommended that the capsules be air dried for about two days.
[0193] Because of the enhanced bioavailability provided by the
present invention, the concentration of the expensive active
peptide component in the pharmaceutical preparation of the
invention may be kept relatively low. Specific formulation examples
incorporating the DMT-DALDA peptide are set forth infra.
[0194] Treatment of Patients
[0195] It is preferred that a single capsule be used at each
administration because a single capsule best provides simultaneous
release of the polypeptide, pH-lowering agent and absorption
enhancers. This is highly desirable because the acid is best able
to reduce undesirable proteolytic attack on the polypeptide when
the acid is released in close time proximity to release of the
polypeptide. Near simultaneous release is best achieved by
administering all components of the invention as a single pill or
capsule. However, the invention also includes, for example,
dividing the required amount of acid and enhancers among two or
more capsules which may be administered together such that they
together provide the necessary amount of all ingredients.
"Pharmaceutical composition," as used herein includes a complete
dosage appropriate to a particular administration to a human
patient regardless of how it is subdivided so long as it is for
substantially simultaneous administration.
[0196] For certain indications, it may be preferred to administer a
first oral pharmaceutical composition in a capsule or tablet which
does not contain a protective acid stable vehicle, such that the
components will be relatively rapidly released in the stomach and
thus be available for immediate pain relief, i.e., within about
10-20 minutes. Subsequently, additional capsules or tablets
formulated according to the invention with a protective vehicle may
then be administered, resulting in bioavailability in the intestine
of the active ingredient after the longer time interval that is
required for gastric emptying, i.e., typically around two
hours.
[0197] In one embodiment of the invention, a sufficient amount of
the peptide (or agonist or partial agonist of vanilloid receptor
VR1) is included in the oral formulation of the invention to
achieve a serum level (i.e, C.sub.max) of the peptide (or agonist
or partial agonist) of from 200 .mu.g/ml to 20 ng/ml, and, more
preferably, from 200 .mu.g/ml to 2 ng/ml. Dosage levels of the
active peptide (and/or the agonist or partial agonist) for
achieving the above serum levels preferably range from 100 .mu.g to
10 mg and more preferably, from 100 .mu.g to 1 mg. With respect to
all of the dosages recommended herein, however, the attending
clinician should monitor individual patient response and adjust the
dosage accordingly. Moreover, except where otherwise stated, the
preferred dosage of the active compounds of the invention is
identical for both therapeutic and prophylactic purposes. The
dosage for each active component discussed herein is the same,
regardless of the disease being treated (or prevented).
Furthermore, except where otherwise indicated, the terms "compound"
and "composition", and any associated molecular structure may
include any possible stereoisomers thereof, in the form of a
racemic mixture or in optically active form.
[0198] Except where otherwise noted, or where apparent from
context, dosages herein refer to weight of active compounds
unaffected by pharmaceutical excipients, diluents, carriers or
other ingredients, although such additional ingredients are
desirably included.
[0199] Experimental Results
[0200] The following examples are provided only for the purpose of
illustration and are not to be construed as limiting the invention
in any manner.
[0201] Applicants have surprisingly discovered, through the use of
in vivo tests involving, respectively, rats and dogs, that
administering Dmt-DALDA in the oral formulation described herein
provides unexpected improvements in bioavailability of the subject
peptide.
[0202] With regard to the first series of tests, i.e., on rats, the
improved effect is demonstrated by comparing the curves for
Formulated DALDA vs. Unformulated DALDA in FIG. 1. In the
experiments represented in the subject Figure, six anesthetized
rats (which were color-coded as: red, white, blue, orange, green
and yellow) were given 0.7 mL Dmt-DALDA (1.6 mg/mL) with a syringe
through a 27 gauge needle into the duodenum. This injection
procedure was followed due to the technical difficulty inherent in
preparing capsules which can be swallowed by small animals the size
of a rat. The intraduodanal injection, therefore, mimics the
release of the components of an enteric-coated capsule formulation
which would pass through the esophagus and stomach and release its
contents in the duodenum. Three of the rats (red, white and blue)
were given Unformulated Dmt-DALDA in which there were no additional
components (i.e., other than the Dmt-DALDA), while the other three
rats (orange, green and yellow) were given Formulated Dmt-DALDA
which included, in addition to the Dmt-DALDA, 0.5M citric acid and
lauroyl carnitine (10 mg/ml). Samples of blood were taken from the
carotid artery through an indwelling catheter before and 5, 15, 30,
60 and 120 minutes after the administration of the respective
formulations (i.e., Formulated and Unformulated).
[0203] The blood samples were centrifuged and the resulting plasma
supernatants were stored frozen at -20.degree. C. The plasma
samples were subsequently analyzed for Dmt-DALDA by
high-performance liquid chromatography (HPLC) through a
50.times.4.6 mm polysulfoethyl-aspartamid- e column with a mobile
phase of 15.4 mM potassium phosphate (pH 3), 210 mM sodium
chloride, and 25% acrylonitrile at a flow rate of 1.5 mL/min.
Peptide was detected with an ultraviolet (UV) detector set at a
wavelength of 210 nm. The results show that Dmt-DALDA was virtually
undetectable in rats given unformulated Dmt-DALDA, whereas as much
as 8 .mu.g/mL of Dmt-DALDA was detected in rats given Dmt-DALDA
formulated in citric acid and lauroyl carnitine. These results
clearly demonstrate that formulating Dmt-DALDA in an oral
formulation according to the present invention increases the
C.sub.max 19-fold and the AUC 110-fold compared to the unformulated
peptide (see Table II below). Table I (below) sets forth the values
upon which the curves in FIG. 1 are based. Table I, moreover,
provides the standard deviations for the data obtained regarding
each of the test rats, which standard deviations are also indicated
in FIG. 1.
1TABLE I unformulated red white blue min .mu.g/mL .mu.g/mL .mu.g/mL
avg sdev sem 0 0.00 0.00 0.00 0.00 0.00 0.00 5 1.54 0.00 0.00 0.51
0.89 0.51 15 0.00 0.00 0.00 0.00 0.00 0.00 30 0.00 0.00 0.00 0.00
0.00 0.00 60 0.00 0.00 0.00 0.00 0.00 0.00 120 0.00 0.00 0.00 0.00
0.00 0.00 formulated min orange green yellow avg sdev sem 0 0.00
0.00 0.00 0.00 0.00 0.00 5 14.15 2.74 7.19 8.03 5.75 3.32 15 0.80*
4.19 10.75 7.47 4.64 3.28 30 12.02 3.21 10.37 8.53 4.69 2.71 60
died 2.40 7.10 4.75 3.32 2.35 120 0.00 2.29 1.14 1.62 1.14 *poor
sampling, not included in mean
[0204] Table II (below) summarizes the pharmacokinetic parameters
in rats of orally administered unformulated and formulated
Dmt-DALDA as those terms are defined above. Data for the individual
rats shown in FIG. 1 are summarized. C.sub.max refers to the
maximum concentration of peptide detected in the rat plasma. The
area under the curve (AUC) is a measure of the extent of peptide
absorption and is calculated by the trapezoidal rule from a plot of
peptide concentration as a function of time.
[0205] T.sub.max indicates when the maximum concentration of the
Dmt-DALDA in the blood serum was obtained.
2TABLE II Unformulated Red White Blue Avg (n = 3) Rat DALDA DALDA
DALDA DALDA Cmax (.mu.g/mL) 1.54 0.00 0.00 0.51 AUC (.mu.g/mL-min)
11.52 0.00 0.00 3.84 Tmax (min) 5.00 5.00 Formulated Orange Green
Yellow Avg (N = 3) Rat DALDA DALDA DALDA DALDA Cmax (.mu.g/mL)
14.15 4.19 10.75 9.69 AUC (.mu.g/mL-min) 206.28 253.16 809.91
423.12 Tmax (min) 5.00 15.00 15.00 11.67
[0206] As shown in Table II, the C.sub.max and AUC for Dmt-DALDA
was significantly enhanced when the peptide was administered in a
"formulated" solution containing citric acid (pH-lowering agent)
and lauroyl carnitine (absorption enhancer).
[0207] A second series of tests was carried out, as noted above,
using beagle dogs. The improved bioavailability of orally
administered Dmt-DALDA is demonstrated in this second series of
tests by comparing the curves for (1) non-enteric coated salmon
calcitonin (sCT) and (2) non-enteric coated Dmt-DALDA (DALDA) in
FIG. 2A with the curves for (3) enteric coated sCT and (4) enteric
coated DALDA in FIG. 2B. In the experiments represented in FIGS. 2A
and 2B, size 00 HPLC capsules were each filled with 758 mg of a
powdered blend consisting of citric acid (643 mg), lauroyl
carnitine (66 mg), talc (33 mg), salmon calcitonin (sCT) (13 mg)
and Dmt-DALDA (2.4 mg). Half of the capsules were coated with an
enteric coating solution of L30D-55, while the remaining 50% of the
capsules were not coated. Four fasted dogs were each given 1
uncoated capsule, and 2 weeks later they were each given an enteric
coated capsule. After administration of each capsule, samples of
blood were taken at 15 minute intervals from an indwelling catheter
for up to 4 hours. The blood samples were centrifuged and the
resulting plasma supernatants were stored frozen at -20.degree. C.
The plasma samples were subsequently analyzed for sCT by a direct
ELISA, and for Dmt-DALDA by HPLC-mass spectrometry performed as set
forth in Wan, H. and Desiderio, D., Quantitation of
[DMT.sup.1]DALDA in ovine plasma by on-line liquid
chromatography/quadrapole time-of-flight mass spectrometry, Rapid
Communications in Mass Spectrometry, 2003; 17, 538-546, the
contents of which are incorporated herein by reference.
[0208] The results summarized in FIGS. 2A and 2B as plasma peptide
concentration normalized to a 1 mg dose as a function of time
relative to the average T.sub.max, (i.e., the time at which the
maximum amount of peptide was detected) indicate that both
peptides, i.e., sCT and Dmt-DALDA, were detected in dogs given
uncoated or enteric coated capsules. However, nearly three times as
much Dmt-DALDA as sCT was detected in dogs given uncoated capsules;
whereas, nearly equal amounts of both peptides were detected in
dogs given enteric coated capsules. Moreover, nearly four times as
much Dmt-DALDA was detected in the plasma of dogs given enteric
coated capsules than those given non-coated capsules. Furthermore,
nearly eight times as much sCT was detected in the plasma of dogs
given enteric coated capsules than non-coated capsules. The maximum
concentration of Dmt-DALDA and sCT in dogs given uncoated capsules
was seen 30 minutes after their administration, whereas the maximum
concentration of these materials when given in coated capsules was
seen 105 minutes after their administration, thus providing the
additional time necessary for the oral formulation to pass through
the stomach while remaining protected from the proteolytic enzymes
therein. These results clearly demonstrate that coating the
capsules with an enteric polymer such that the capsule does not
release its contents until reaching the small intestine
significantly enhances peptide absorption. Table III (below) sets
forth the values upon which the curves in FIGS. 2A and 2B are
based. The results are summarized in the tables as plasma peptide
concentration normalized to a 1 mg dose as a function of time.
Table III, moreover, provides the standard deviations for the data
obtained regarding each of the test dogs, which standard deviations
are also indicated in FIGS. 2A and 2B.
3 TABLE III Dog 1 Dog 2 Dog 3 Dog 4 sCT DALDA sCT DALDA sCT DALDA
sCT DALDA Min pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL
Non-enteric Coated Capsules Containing Citric Acid and Lauroyl
Carnitine 0 0 0 0 0 0 0 0 0 15 0 0 0 0 0 0 0 0 30 2648 4108 3148
6473 0 0 971 5456 45 1343 5104 2151 5602 278 5788 60 561 4066 897
5726 163 4481 75 273 2407 229 4523 101 2934 90 140 2780 182 3568 69
2382 105 121 1938 122 3444 45 3054 120 89 1627 69 2614 26 1759 135
51 1158 44 2697 16 1627 150 31 830 39 2407 12 1544 165 23 913 22
2531 0 1324 180 16 705 15 2075 0 1191 195 11 581 0 1328 0 851 210 0
544 0 1867 0 722 225 0 436 0 1535 0 672 240 0 402 0 1494 0 556
Enteric Coated Capsules Containing Citric Acid and Lauroyl
Carnitine 0 0 0 0 0 0 0 0 0 15 0 0 0 0 0 0 0 0 30 407 0 0 0 0 0 0 0
45 22650 29440 0 0 0 0 0 0 60 25136 25224 0 0 0 0 0 0 75 6444 19768
0 0 0 0 0 0 90 8167 19021 0 0 0 0 0 0 105 4344 12324 0 0 0 0 13111
4577 120 3193 8108 0 0 0 0 13147 12116 135 2710 10714 0 0 13219
21494 6841 10207 150 1706 9349 0 0 10151 19378 4251 6307 165 1283
6743 0 0 4410 12697 2448 5158 180 1301 5502 0 0 2983 9100 1468 3884
195 459 5008 0 0 1825 4876 1192 2896 210 347 3021 0 0 1194 4772 867
2664 225 331 2896 0 0 734 4884 686 2490 240 179 2527 0 0 626 3651
515 1851
[0209] Table IV (below) summarizes the pharmacokinetic parameters
in dogs of orally administered sCT and Dmt-DALDA when administered
in non-enteric coated versus enteric coated capsules. Peptide was
not detected from 1 dog in each group due to (a) Dog 3 vomiting the
uncoated capsule and (b) delayed gastric emptying in Dog 2 provided
with an enteric coated capsule. C.sub.max and AUC are as defined
with regard to Table II above.
4 TABLE IV Dog Dog 1 Dog 2 Dog 3 Dog 4 Avg (n = 3) dmt- dmt- dmt-
dmt- dmt- sCT DALDA sCT DALDA sCT DALDA sCT DALDA sCT DALDA
Non-Enteric Capsule Cmax (pg/mL) 2648 5104 3148 6473 0 0 971 5788
2256 5788 AUC (pg/mL-min) 79620 410944 103772 707054 0 0 25227
510934 69539 542977 Tmax (min) 30 45 30 30 30 45 30 40 Enteric
Capsule Cmax (pg/mL) 25136 29440 0 0 13219 21494 13147 12116 17167
21017 AUC (pg/mL-min) 1178504 2375695 0 0 522432 1185373 664016
768361 788317 1443143 Tmax (min) 60 45 135 135 120 120 105 100
[0210] As shown in Table IV, the C.sub.max and AUC values for both
sCT and Dmt-DALDA were significantly enhanced when the peptides
were administered in enteric coated capsules versus in non
enteric-coated capsules. The C.sub.max of enteric coated Dmt-DALDA
is 4-fold higher than that of non enteric coated Dmt-DALDA.
Surprisingly, the bioavailability of both enteric coated and
non-coated Dmt-DALDA is better than that of sCT. It would be
expected that the bioavailability of a molecule such as Dmt-DALDA,
which is positively charged and hydrophilic, would be extremely
poor. The data indicates that when this peptide is administered in
combination with the ingredients of the present invention, either
with or without an enteric coating, however, the bioavailability is
unexpectedly increased to the point where it is superior to that of
sCT, a molecule that has previously been shown to be highly
bioavailable when formulated according to the present
invention.
[0211] The improvement in oral bioavailability achieved with the
Dmt-DALDA peptide in accordance with the present invention, i.e.,
H-2,6-dimethyltyrosine-D-Arginine-Phenylalanine-Lysine-NH.sub.2, is
believed to adequately support an expectation of similarly improved
results with the remaining active agents described herein. With no
intention to be bound by theory, applicants submit in explanation
therefor that DALDA and other analgesic peptides that are analogs
of dermorphin or deltorphin, as well as other opioid peptides, are
highly charged molecules. For example, Dmt-DALDA has a 3+ net
charge. It would be expected that these net positive charges would
cause the peptide to bind to the negatively charged mucous layer
that lines the gastrointestinal tract, thus reducing the
bioavailability of the peptide. It is believed, although applicants
are not to be bound by such belief, that the negatively charged
citric acid (i.e., the pH-lowering agent), which is in excess in
the formulation, would neutralize some or all of the positive
charges on the peptide and thus prevent the interaction between the
peptide and the mucous layer. Additionally, applicants believe that
the positive charge on the acylcarnitine absorption enhancer
neutralize the negative charge on the mucous layer in the immediate
vicinity of the release of the capsule or tablet contents, and
therefore would further prevent the positively charged peptide from
binding with the mucous layer. The peptide thus remains available
to traverse the epithelial layer in the gastrointestinal tract by
paracellular transport through the tight junctions between cells,
which are relaxed due to the presence of the acylcarnitine. One of
ordinary skill in this art would therefore reasonably expect that
the additional active compounds described herein, e.g., the various
peptides and their prodrugs, which have a similar size, charge and
hydrophilicity to Dmt-DALDA, would themselves achieve an
unexpectedly improved degree of bioavailability when administered
in the oral formulation taught and claimed herein.
[0212] Although the present invention has been described in
relation to particular embodiments thereof, many other variations
and modifications and other uses will become apparent to those
skilled in the art. The present invention therefore is not limited
by the specific disclosure herein, but only by the claims.
* * * * *