U.S. patent application number 15/190305 was filed with the patent office on 2016-10-13 for compositions for delivering peptide yy and pyy agonists.
The applicant listed for this patent is Emisphere Technologies, Inc.. Invention is credited to Steven DINH, Maria I. GOMEZ-ORELLANA, Huaizhen WANG.
Application Number | 20160296599 15/190305 |
Document ID | / |
Family ID | 35839770 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160296599 |
Kind Code |
A1 |
DINH; Steven ; et
al. |
October 13, 2016 |
COMPOSITIONS FOR DELIVERING PEPTIDE YY AND PYY AGONISTS
Abstract
The present invention provides a composition (e.g., a
pharmaceutical composition) comprising at least one delivery agent
compound and at least one of peptide YY (PYY) and a PYY agonist.
Preferably, the composition includes a therapeutically effective
amount of peptide YY or the PYY agonist and the delivery agent
compound. The composition of the present invention facilitates the
delivery of PYY, a PYY agonist, or a mixture thereof and increases
its bioavailability compared to administration without the delivery
agent compound. PPY and PYY agonists possess activity as agents to
reduce nutrient availability, including reduction of food
intake.
Inventors: |
DINH; Steven; (Briarcliff
Manor, NY) ; WANG; Huaizhen; (Chappaqua, NY) ;
GOMEZ-ORELLANA; Maria I.; (New Rochelle, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Emisphere Technologies, Inc. |
Roseland |
NJ |
US |
|
|
Family ID: |
35839770 |
Appl. No.: |
15/190305 |
Filed: |
June 23, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11571862 |
Jul 1, 2009 |
9399054 |
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PCT/US05/24599 |
Jul 12, 2005 |
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15190305 |
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60587751 |
Jul 12, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 38/22 20130101; A61P 3/10 20180101; A61P 5/50 20180101; A61P
9/10 20180101; A61P 9/00 20180101; A61P 3/02 20180101; A61K 9/2095
20130101; A61K 9/0056 20130101; A61P 9/12 20180101; A61P 43/00
20180101; A61K 9/2013 20130101; A61P 3/06 20180101; A61P 3/04
20180101; A61P 7/00 20180101; A61K 9/2072 20130101 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61K 9/20 20060101 A61K009/20; A61K 9/00 20060101
A61K009/00 |
Claims
1. A dosage unit form for oral administration comprising (a) at
least one peptide YY, a peptide YY agonist, or a mixture thereof,
and (b) a delivery agent of the formula ##STR00008## or a salt
thereof, wherein: Ar is phenyl or naphthyl; Ar is optionally
substituted with one or more of --OH, halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy or
C.sub.1-C.sub.4 haloalkoxy; R.sup.7 is selected from
C.sub.4-C.sub.20 alkyl, C.sub.4-C.sub.20 alkenyl, phenyl, naphthyl,
(C.sub.1-C.sub.10 alkyl)phenyl, (C.sub.1-C.sub.10 alkenyl)phenyl,
(C.sub.1-C.sub.10 alkyl) naphthyl, (C.sub.1-C.sub.10) alkenyl)
naphthyl, phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10
alkenyl), naphthyl(C.sub.1-C.sub.10 alkyl), or
naphthyl(C.sub.1-C.sub.10 alkenyl); R.sup.8 is selected from
hydrogen, C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.4 alkenyl,
C.sub.1 to C.sub.4 alkoxy, and C.sub.1-C.sub.4 haloalkoxy; R.sup.7
is optionally substituted with C.sub.1 to C.sub.4 alkyl, C.sub.2 to
C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy C.sub.1-C.sub.4
haloalkoxy, --OH, --SH, and --CO.sub.2R.sup.9, or any combination
thereof; R.sup.9 is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2
to C.sub.4 alkenyl; and R.sup.7 is optionally interrupted by
oxygen, nitrogen, sulfur or any combination thereof.
2. A dosage unit form for oral administration comprising (a) at
least one peptide YY, a peptide YY agonist, or a mixture thereof,
and (b) a delivery agent of the formula ##STR00009## or a salt
thereof, wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently H, --OH, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8,
--NO.sub.2, --NR.sup.9R.sup.10, or
--N.sup.+R.sup.9R.sup.10R.sup.11(R.sup.12)--; R.sup.5 is H, --OH,
--NO.sub.2, halogen, --CF.sub.3, --NR.sup.14R.sup.15,
--N.sup.+R.sup.14R.sup.15R.sup.16 (R.sup.13).sup.-, amide,
C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12 alkyl, C.sub.2-C.sub.12
alkenyl, carbamate, carbonate, urea, or --C(O)R.sup.18; R.sup.5 is
optionally substituted with halogen, --OH, --SH, or --COOH; R.sup.5
is optionally interrupted by O, N, S, or --C(O)--; R.sup.6 is a
C.sub.1-C.sub.12 alkylene, C.sub.2-C.sub.12 alkenylene, or arylene;
R.sup.6 is optionally substituted with a C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sup.8; R.sup.6 is optionally
interrupted by O or N; R.sup.7 is a bond or arylene; R.sup.7 is
optionally substituted with --OH, halogen, --C(O)CH.sub.3,
--NR.sup.10R.sup.11, or --N.sup.+R.sup.10R.sup.11R.sup.12
(R.sup.13).sup.-; R.sup.8 is H, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, or --NH.sub.2; R.sup.9, R.sup.10,
R.sup.11, and R.sup.12 independently H or C.sub.1-C.sub.10 alkyl;
R.sub.13 is a halide, hydroxide, sulfate, tetrafluoroborate, or
phosphate; and R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, --C(O)R.sup.17; R.sup.17 is --OH,
C.sub.1-C.sub.10 alkyl, or C.sub.2-C.sub.12 alkenyl; and R.sup.18
is H, C.sub.1-C.sub.6 alkyl, --OH, --NR.sup.14R.sup.15, or
N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13).
3. A dosage unit form for oral administration comprising (a) at
least one peptide YY, a peptide YY agonist, or a mixture thereof,
and (b) a delivery agent of the formula ##STR00010## or a salt
thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
independently H, --CN, --OH, --OCH.sub.3, or halogen, at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN; and
R.sup.6 is C.sub.1-C.sub.12 linear or branched alkylene,
alkenylene, arylene, alkyl(arylene) or aryl(alkylene).
4. The dosage unit form of claim 1, wherein the delivery agent is
selected from the group consisting of the monosodium salt of
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, the monosodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the monosodium salt
of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, the monosodium
salt of 8-(2,6-dihydroxybenzoylamino)octanoic acid, the monosodium
salt of 8-(2-hydroxy-5-bromobenzoylamino)actanoic acid, the
monosodium salt 8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,
the monosodium salt of 8-(2-hydroxy-5-iodobenzoylamino)octanoic
acid, the monosodium salt of
8-(2-hydroxy-5-methylbenzoylamino)octanoic acid, the monosodium
salt of 8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid, the
monosodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic
acid, the monosodium salt of 8-(3-hydroxyphenoxy)octanoic acid, the
monosodium salt of 8-(4-hydroxyphenoxy)octanoic acid, the
monosodium salt of 6-(2-cyanophenoxy)hexanoic acid, the monosodium
salt of 8-(2-hydroxyphenoxy)octyl-diethanolamine, disodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the disodium salt of
8-(4-hydroxyphenoxy)octanoate, the monosodium salt of
8-(4-hydroxyphenoxy)octanoate, the disodium salt of
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, and the disodium
salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid.
5. The dosage unit form of claim 1 wherein the delivery agent is
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceutically
acceptable salt thereof.
6. The dosage unit form of claim 1 wherein the delivery agent is
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid or a pharmaceutically
acceptable salt thereof.
7. The dosage unit form of claim 1, wherein the peptide YY agonist
is selected from the functional domain of PYY, active fragments of
PYY, derivatives of PYY, fragments of PYY, or analogs of PYY.
8. The dosage unit form of claim 1, wherein the peptide YY agonist
is PYY[3-36].
9. A dosage unit form comprising: (A) the dosage unit form of claim
1; and (B) (a) an excipient, (b) a diluent, (c) a disintegrant, (d)
a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing
vehicle, or (h) any combination thereof.
10. The dosage unit form of claim 9, wherein the dosage unit form
is in the form of a tablet, a capsule, a particle, a powder, a
sachet, or a liquid.
11. The dosage unit form of claim 9, wherein the dosing vehicle is
a liquid selected from the group consisting of water, aqueous
propylene glycol, phosphate buffer, 1,2-propane diol, ethanol, and
any combination thereof.
12. A method for administering an effective amount of peptide YY or
a peptide YY agonist to a patient in need of thereof, comprising
the step of orally administering the dosage unit form of claim
1.
13. The method of claim 12 wherein the peptide YY agonist is
PYY[3-36] and the delivery agent is
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid or
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid or a pharmaceutically
acceptable salt thereof.
14. A method of treating obesity in a patient in need thereof,
comprising the step of orally administering to the patient an
effective amount of the dosage unit form of claim 1.
15. A method of treating a condition or disorder that may be
alleviated by reducing nutrient availability in a patient in need
thereof, comprising the step of orally administering to an animal
an effective amount of the dosage unit form of claim 1.
16. The method of claim 15 wherein the condition or disorder is
selected from the group consisting of hypertension, dyslipidemia,
cardiovascular risk, an eating disorder, insulin-resistance,
obesity and diabetes mellitus, or any combination thereof.
17. The method of claim 15 wherein the condition or disorder is
selected from the group consisting of cancer, cachexia and
malnutrition, or any combination thereof.
18. A method of reducing nutrient uptake in a patient in need
thereof, comprising the step of orally administering an effective
amount of the dosage unit form of claim 1.
19. A method of improving the lipid profile in a patient in need
thereof, comprising the step of orally administering an effective
amount of the dosage unit form of claim 1.
20. A method of improving the bioavailability of a peptide YY, a
peptide YY agonist, or both, in an animal, the method comprising
the step of orally administering the dosage unit form of claim
1.
21. (canceled)
Description
[0001] This application claims the priority date of and
incorporates by reference U.S. Provisional Patent Application No.
60/587,751, filed Jul. 12, 2004, and incorporates by reference U.S.
patent application Ser. No. 10/846,954, filed May 14, 2004, U.S.
Provisional Patent Application No. 60/470,905, filed May 14, 2003,
U.S. Provisional Patent Application No. 60/471,114, filed May 15,
2003, U.S. Provisional Patent Application No. 60/506,702, filed
Sep. 25, 2003, and U.S. Provisional Patent Application No.
60/536,697, filed Jan. 14, 2004.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions for delivering
peptide YY (PYY) and PYY agonists to a target. These composition
include compounds that are well suited for forming non-covalent
mixtures with PYY and PYY agonists for administration to animals.
Methods for preparation, administration and treatment are also
disclosed.
BACKGROUND OF THE INVENTION
[0003] Current antiobesity drugs have limited efficacy and numerous
side effects. Crowley, V. E., Yeo, G. S. & O'Rahilly, S., Nat.
Rev. Drug Discov 1, 276-86 (2002). With obesity reaching epidemic
proportions worldwide, there is a pressing need for the development
of adequate therapeutics in this area. In recent years, hormones
and neuropeptides involved in the regulation of appetite, body
energy expenditure, and fat mass accumulation have emerged as
potential antiobesity drugs. McMinn, J. E., Baskin, D. G. &
Schwartz, M. W., Obes Rev 1:37-46 (2000), Drazen, D. L. &
Woods, S. C., Curr Opin Clin Nutr Metab Care 6:621-629 (2003). At
present, however, these peptides require parenteral administration.
The prospect of daily injections to control obesity is not very
encouraging and may limit the use of these drugs.
[0004] One such peptide, PYY, is secreted postprandially by
endocrine cells of the distal gastrointestinal tract and acts at
the hypothalamus signaling satiety. Batterham, R. L. et al., Nature
418:650-654 (2002). Recent studies have shown that fasting and
postprandial PYY levels are low in obese subjects, which may
account for their high appetite and food consumption. When
administered intravenously, it suppresses appetite and food intake
in both lean and obese subjects. Batterham, R. L. et al., N Engl J
Med 349:941-948 (2003). Other peptides from the pancreatic peptide
(PP) family, like peptide YY fragments (e.g. PYY[3-36]), and PYY
agonists (including those not in the PP family) also suppress
appetite. Its oral activity, however, is negligible due to its low
absorption and rapid degradation in the gastrointestinal tract.
[0005] PYY Cancer, Cachexia and Malnutrition: PYY is also secreted
secreted by various cancer cells: lung, ovarian, prostate, breast
and Barrett's adenocarcinoma, and could act as a marker for or a
target for treatment of these other malignancies. Treatment
modalities could be directed toward the effects of PYY on cellular
apoptosis and/or vascular endothelial growth factor.
[0006] PYY has been identified in several carcinoid tumors, and a
decreased expression of PYY may be relevant to the development and
progression of colon adenocarcinoma. Treatment with PYY decreases
growth in pancreatic and breast tumors, most likely through a
reduction in intracellular cAMP. Furthermore, PYY has
antiproliferative and proapoptotic effects in Barrett's cancer
cells. Combined PYY and vitamin E have significant additive
antiproliferative effects on breast cancer cell lines regardless of
their hormone receptor status. In addition, PYY and vitamin E have
growth inhibitory effects on hormone-refractory prostate and
pancreatic cancer cells. A biologically active form of vitamin E,
alpha-tocopherol succinate (ATS), has been shown to induce
apoptosis of hormone-refractory prostate cancer in vitro and
inhibit cell growth in vivo.
[0007] Taken together, the evidence suggests a potential role for
PYY as a therapeutic agent for the treatment or attenuation of
multiple cancers.
[0008] In cancer patients, PYY may also improve malnutrition that
results from iatrogenic causes or cachexia associated with advanced
disease. PYY plays a significant role in multiple aspects of cancer
from regulation of cell growth to potential therapeutic
applications.
[0009] PYY and Acute Pancreatitis: Acute pancreatitis (AP) is a
disease characterized by inflammation. PYY inhibits NF-k
translocation to acinar nuclei in TNF-a-induced AP. Targeted
inhibition of transcription factors with PYY may have therapeutic
potential in attenuating the progression of pancreatitis.
[0010] PYY and Other Gastrointestinal Uses: Because of its slowing
effects on gastric motility, PYY has additional potential uses, for
example in spastic/irritable bowel, diabetes gastroenteropathy,
inflammatory bowel diseases, celiac disease, systemic sclerosis and
post-intestinal resection state.
[0011] Jean Reubi, Mathias Gugger, Beatrice Waser Eur J Nucl Med
Mol Imaging. 2002 July; 29(7):855-62. Epub 2002 Apr. 20 .
Co-expressed peptide receptors in breast cancer as a molecular
basis for in vivo multireceptor tumor targeting. Grise K R,
Rongione A J, Laird E C, McFadden D W. Peptide YY inhibits growth
of human breast cancer in vitro and in vivo. J Surg Res. 1999
April; 82(2):151-5. Matsuda K, Maehama T, Kanazawa K. Strumal
carcinoid tumor of the ovary: a case exhibiting severe constipation
associated with PYY. Gynecol Oncol. 2002 October; 87(1):143-5.
Yamashita Y, Miyahara E, Shimizu K, Toge T, Adrian T E. Screening
of gastrointestinal hormone release in patients with lung cancer.
In Vivo. 2003 March-April; 17(2):193-5. Yu A, Somasundar P,
Balsubramaniam A, Rose A T, Vona-Davis L, McFadden D W. J Surg Res.
2002 Jun. 1; 105(1):65-8. Vitamin E and the Y4 agonist BA-129
decrease prostate cancer growth and production of vascular
endothelial growth factor.
[0012] At least five distinct neuropeptide Y (NPY) receptors are
known to exist, and studies suggest that at least one additional
subtype of NPY receptor may exist in rat brains. Dumont, Y., Moyse,
E., Fournier, A., Quirion, R., J. Pharmacol Exp. Ther., Jun. 9,
2005; Evidence for the Existence of an Additional Class of
Neuropeptide Y Receptor Sites in the Rat Brain.
[0013] In the delivery to animals of PYY and PYY agonist, barriers
are imposed by the body. Examples of physical barriers are the
skin, lipid bi-layers and various organ membranes that are
relatively impermeable to certain active agents but must be
traversed before reaching a target, such as the circulatory system.
Chemical barriers include, but are not limited to, pH variations in
the gastrointestinal (GI) tract and degrading enzymes.
[0014] These barriers are of particular significance in the design
of oral delivery systems. Oral delivery of PYY and PYY agonist
would be the route of choice for administration to animals if not
for such biological, chemical, and physical barriers. These agents
may be rapidly rendered ineffective or destroyed in the
gastro-intestinal tract by acid hydrolysis, enzymes, and the like.
In addition, the size and structure of macromolecular drugs may
prohibit absorption. As a result, the oral administration of
protein and peptide drugs is challenging due, in part, to their low
absorption and rapid degradation.
[0015] Earlier methods for orally administering vulnerable
pharmacological agents have relied on the co-administration of
adjuvants (e.g., resorcinols and non-ionic surfactants such as
polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to
increase artificially the permeability of the intestinal walls, as
well as the co-administration of enzymatic inhibitors to inhibit
enzymatic degradation. Liposomes have also been described as drug
delivery systems for insulin and heparin. However, broad spectrum
use of such drug delivery systems is precluded in part because: (1)
the systems require toxic amounts of adjuvants or inhibitors; (2)
suitable low molecular weight cargos, i.e., active agents, are not
available; (3) the systems exhibit poor stability and inadequate
shelf life; (4) the systems are difficult to manufacture; (5) the
systems fail to protect the active agent (cargo); (6) the systems
adversely alter the active agent; or (7) the systems fail to allow
or promote absorption of the active agent.
[0016] More recently, proteinoid microspheres have been used to
deliver pharmaceuticals. See, for example, U.S. Pat. Nos.
5,401,516; 5,443,841; and Re. 35,862. In addition, certain modified
amino acids have been used to deliver pharmaceuticals. See, for
example, U.S. Pat. Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888;
and 5,866,536.
[0017] According to Batterham et al., Nature 418:650-654 (2002),
which is hereby incorporated by reference, the peptide YY [3-36]
system may provide a therapeutic target for the treatment of
obesity.
[0018] International Publication No. WO 02/47712 and U.S. Patent
Publication No. 2002/0141985 disclose methods for treating obesity
and diabetes with peptide YY and peptide YY agonists, such as
peptide YY[3-36].
[0019] International Publication No. WO 2004/104018 discloses a
composition comprising at least one delivery agent compound and at
least one of peptide YY (PYY) and a PYY agonist.
[0020] There is still a need for simple, inexpensive delivery
systems for delivering peptide YY and PYY agonists which are
non-invasive and which are convenient, so as to increase patient
compliance and acceptability.
SUMMARY OF THE INVENTION
[0021] The present invention provides a composition (e.g., a
pharmaceutical composition) comprising (a) at least one delivery
agent compound and (b) peptide YY (PYY), a PYY agonist, or a
mixture thereof. Preferably, the composition includes a
therapeutically effective amount of peptide YY and/or the PYY
agonist and the delivery agent compound. The composition of the
present invention facilitates the delivery of PYY and/or the PYY
agonist and increases its bioavailability compared to
administration without the delivery agent compound. PYY and PYY
agonists possess activity as agents to reduce nutrient
availability, including reduction of food intake.
[0022] Preferred delivery agent compounds include, but are not
limited to, N-(8-[2-hydroxybenzoyl]amino)caprylic acid and
N-(10-[2-hydroxybenzoyl]amino)decanoic acid and salts thereof, and
solvates and hydrates thereof. In a preferred embodiment, the salt
is the sodium salt, such as the monosodium salt.
[0023] In one preferred embodiment, the composition comprises
peptide YY, a PYY agonist, or a mixture thereof, and at least one
delivery agent of the following structure or a salt thereof:
##STR00001##
wherein
[0024] Ar is phenyl or naphthyl;
[0025] Ar is optionally substituted with one or more of --OH,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkenyl, alkoxy or
C.sub.1-C.sub.4 haloalkoxy;
[0026] R.sup.7 is selected from C.sub.4-C.sub.20 alkyl,
C.sub.4-C.sub.20 alkenyl, phenyl, naphthyl, (C.sub.1-C.sub.10
alkyl) phenyl, (C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10
alkyl) naphthyl, (C.sub.1-C.sub.10 alkenyl) naphthyl,
phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10 alkenyl),
naphthyl(C.sub.1-C.sub.10 alkyl), or naphthyl(C.sub.1-C.sub.10
alkenyl);
[0027] R.sup.8 is selected from hydrogen, C.sub.1 to C.sub.4 alkyl,
C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, and
C.sub.1-C.sub.4 haloalkoxy;
[0028] R.sup.7 is optionally substituted with C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --OH, --SH, --CO.sub.2R.sup.9, or any
combination thereof;
[0029] R.sup.9 is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2 to
C.sub.4 alkenyl.
[0030] R.sup.7 is optionally interrupted by oxygen, nitrogen,
sulfur or any combination thereof. In some embodiments, the
compounds are not substituted with an amino group in the position
alpha to the acid group.
[0031] In another preferred embodiment, the composition comprises
peptide YY, a PYY agonist, or a mixture thereof, and at least one
delivery agent of the following structure or a salt thereof:
##STR00002##
wherein
[0032] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--OH, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8, --NO.sub.2,
--NR.sup.9R.sup.10, or --N.sup.+R.sup.9R.sup.10R.sup.11
(R.sup.12).sup.-;
[0033] R.sup.5 is H, --OH, --NO.sub.2, halogen, --CF.sub.3,
--NR.sup.14R.sup.15, --N.sup.+R.sup.14R.sup.15R.sup.16
(R.sup.13).sup.-, amide, C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.12 alkenyl, carbamate, carbonate, urea, or
--C(O)R.sup.18;
[0034] R.sup.5 is optionally substituted with halogen, --OH, --SH,
or --COOH;
[0035] R.sup.5 is optionally interrupted by O, N, S, or
--C(O)--;
[0036] R.sup.6 is a C.sub.1-C.sub.12 alkylene, C.sub.2-C.sub.12
alkenylene, or arylene;
[0037] R.sup.6 is optionally substituted with a C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sup.8;
[0038] R.sup.6 is optionally interrupted by O or N;
[0039] R.sup.7 is a bond or arylene;
[0040] R.sup.7 is optionally substituted with --OH, halogen,
--C(O)CH.sub.3, --NR.sup.10R.sup.11, or
--N.sup.+R.sup.10R.sup.11R.sup.12 (R.sup.13).sup.-;
[0041] each occurrence of R.sup.8 is independently H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, or --NH.sub.2;
[0042] R.sup.9, R.sup.10, R.sup.11, and R.sup.12 independently H or
C.sub.1-C.sub.10 alkyl;
[0043] R.sup.13 is a halide, hydroxide, sulfate, tetrafluoroborate,
or phosphate;
[0044] R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, or --C(O)R.sup.17;
[0045] R.sup.17 is --OH, C.sub.1-C.sub.10 alkyl, or
C.sub.2-C.sub.12 alkenyl; and
[0046] R.sup.18 is H, C.sub.1-C.sub.6 alkyl, --OH,
--NR.sup.14R.sup.15, or
N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13).
[0047] Optionally, when R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 are H, and R.sup.7 is a bond then R.sup.6 is not a
C.sub.1-C.sub.6, C.sub.9 or C.sub.10 alkyl.
[0048] Optionally, when R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
H, R.sup.5 is --OH, R.sup.7 is a bond then R.sup.6 is not a
C.sub.1-C.sub.3 alkyl.
[0049] Optionally, when at least one of R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 is not H, R.sup.5 is --OH, R.sup.7 is a bond, then
R.sup.6 is not a C.sub.1-C.sub.4 alkyl.
[0050] Optionally, when R.sup.1, R.sup.2, and R.sup.3 are H,
R.sup.4 is --OCH.sub.3, R.sup.5 is --C(O)CH.sub.3, and R.sup.6 is a
bond then R.sup.7 is not a C.sub.3 alkyl.
[0051] Optionally, when R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are
H, R.sup.3 is --OH, and R.sup.7 is a bond then R.sup.6 is not a
methyl.
[0052] In yet another embodiment the composition comprises peptide
YY, PYY agonist, or a mixture thereof and at least one delivery
agent of the following structure or a salt thereof:
##STR00003##
wherein
[0053] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
independently H, --CN, --OH, --OCH.sub.3, or halogen, at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN;
and
[0054] R.sup.6 is a C.sub.1-C.sub.12 linear or branched alkylene,
alkenylene, arylene, alkyl(arylene) or aryl(alkylene).
[0055] According to one embodiment, when R.sup.1 is --CN, R.sup.4
is H or --CN, and R.sup.2, R.sup.3, and R.sup.5 are H, then R.sup.6
is not methylene ((CH.sub.2).sub.1).
[0056] Also provided is a dosage unit form (e.g., an oral or buccal
dosage unit form) comprising the composition of the present
invention. The dosage unit form may be in the form of a liquid or a
solid, such as a tablet, capsule or particle, including a powder or
sachet.
[0057] Another embodiment is a method for administering peptide YY,
a PYY agonist, or a mixture thereof to an animal in need thereof,
by administering the composition or dosage unit form(s) of the
present invention to the animal. The preferred route of
administration is oral or buccal.
[0058] Another embodiment is a method for administering peptide YY,
a PYY agonist, or a mixture thereof to an animal in need thereof,
by administering the composition or dosage unit form(s) of the
present invention to the animal in a manner to minimize or prevent
formation of antibodies to the peptide YY and/or a PYY agonist.
[0059] Yet another embodiment is a method of losing weight in an
animal (such as a human) in need thereof by administering an
effective amount of the composition or dosage unit form(s) of the
present invention to the animal. In other words, an effective
amount of the delivery agent compound to facilitate the delivery of
the PYY or PYY agonist and an effective amount (e.g., a
therapeutically effective amount) of PYY or PYY agonist are
administered.
[0060] Yet another embodiment is a method of treating obesity in an
animal (such as a human) in need thereof by administering an
effective amount of the composition of the present invention to the
animal.
[0061] Yet another embodiment is a method for treating conditions
or disorders which can be alleviated by reducing nutrient
availability in an animal (such as a human) by administering to the
animal a therapeutically effective amount of the composition or
dosage unit form(s) of the present invention. Such conditions and
disorders, include but are not limited to, hypertension,
dyslipidemia, cardiovascular risk, an eating disorder,
insulin-resistance, obesity, and diabetes mellitus.
[0062] Yet another embodiment is a method of improving the lipid
profile in an animal (such as a human) by administering to the
animal an effective amount of the composition or dosage unit
form(s) of the present invention.
[0063] Yet another embodiment is a method of preparing a
composition of the present invention by mixing at least one
delivery agent compound and at least one of peptide YY and a PYY
agonist.
[0064] Yet another embodiment is a dosage unit form for buccal
administration comprising at least one delivery agent compound and
at least one of peptide YY and a PYY agonist. The dosage unit form
may be, for example, in the form of a solid, such as a tablet or
candy which dissolves in the mouth, a powder, a liquid, or a thin
sheet, or any other form which dissolves and/or sticks to the
interior of the mouth, or facilitates the buccal administration of
PYY or PYY agonist.
[0065] Another embodiment is a method for buccally administering
peptide YY, a PYY agonist, or a mixture thereof to an animal in
need thereof, by buccally administering the composition or dosage
unit form(s) of the present invention to the animal. Preferably, it
is administered in a manner to minimize or prevent formation of
antibodies to the peptide YY and/or a PYY agonist.
[0066] Yet another embodiment is a method for treating conditions
or disorders which can be alleviated by reducing nutrient
availability in an animal (such as a human) by buccally
administering to the animal a therapeutically effective amount of
the composition or dosage unit form(s) of the present invention.
Such conditions and disorders, include but are not limited to,
those described above.
[0067] Yet another embodiment is a method of losing weight in an
animal (such as a human) in need thereof by buccally administering
an effective amount of the composition or dosage unit form(s) of
the present invention to the animal.
[0068] Yet another embodiment is a method of treating obesity in an
animal (such as a human) in need thereof by buccally administering
an effective amount of the composition of the present invention to
the animal.
[0069] Yet another embodiment is a method of improving the lipid
profile in an animal (such as a human) by buccally administering to
the animal an effective amount of the composition or dosage unit
form(s) of the present invention.
[0070] Yet another embodiment is a method of treating or
attenuating one or more cancers in an animal (such as a human) by
buccally administering an effective amount of the composition of
the present invention to the animal.
BRIEF DESCRIPTION OF THE DRAWINGS
[0071] FIG. 1 is a graph of serum PYY concentrations in beagles
versus time after buccal administration of 0.1 mg/kg of PYY and 10
mg/kg of SNAD.
DETAILED DESCRIPTION OF THE INVENTION
[0072] Embodiments of the invention may comprise dosage unit forms
for buccal administration comprising (a) at least one peptide YY, a
peptide YY agonist, or a mixture thereof, and (b) a delivery agent
of the formula
##STR00004##
or a salt thereof, wherein:
[0073] Ar is phenyl or naphthyl;
[0074] Ar is optionally substituted with one or more of --OH,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4 haloalkoxy;
[0075] R.sup.7 is selected from C.sub.4-C.sub.20 alkyl,
C.sub.4-C.sub.20 alkenyl, phenyl, naphthyl. (C.sub.1-C.sub.10
alkyl) phenyl, (C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10
alkyl) naphthyl, (C.sub.1-C.sub.10 alkenyl) naphthyl,
phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10 alkenyl),
naphthyl(C.sub.1-C.sub.10 alkyl), or naphthyl(C.sub.1-C.sub.10
alkenyl);
[0076] R.sup.8 is selected from hydrogen, C.sub.1 to C.sub.4 alkyl,
C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, and
C.sub.1-C.sub.4 haloalkoxy;
[0077] R.sup.7 is optionally substituted with C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --OH, --SH, and --CO.sub.2R.sup.9, or
any combination thereof;
[0078] R.sup.9 is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2 to
C.sub.4 alkenyl; and
[0079] R.sup.7 is optionally interrupted by oxygen, nitrogen,
sulfur or any combination thereof. In some embodiments, the
compounds are not substituted with an amino group in the position
alpha to the acid group.
[0080] Embodiments of the invention may comprise dosage unit forms
for buccal administration comprising (a) at least one peptide YY, a
peptide YY agonist, or a mixture thereof, and (b) a delivery agent
of the formula
##STR00005##
or a salt thereof; wherein
[0081] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently H,
--OH, halogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, --C(O)R.sup.8, --NO.sub.2,
--NR.sup.9R.sup.10, or --N.sup.+R.sup.9R.sup.10R.sup.11
(R.sup.12).sup.-;
[0082] R.sup.5 is H, --OH, --NO.sub.2, halogen, --CF.sub.3,
--NR.sup.14R.sup.15, --N.sup.+R.sup.14R.sup.15R.sup.16
(R.sup.13).sup.-, amide, C.sub.1-C.sub.12 alkoxy, C.sub.1-C.sub.12
alkyl, C.sub.2-C.sub.12 alkenyl, carbamate, carbonate, urea, or
--C(O)R.sup.18;
[0083] R.sup.5 is optionally substituted with halogen, --OH, --SH,
or --COOH;
[0084] R.sup.5 is optionally interrupted by O, N, S, or
--C(O)--;
[0085] R.sup.6 is a C.sub.1-C.sub.12 alkylene, C.sub.2-C.sub.12
alkenylene, or arylene;
[0086] R.sup.6 is optionally substituted with a C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, --OH, --SH,
halogen, --NH.sub.2, or --CO.sub.2R.sup.8;
[0087] R.sup.6 is optionally interrupted by O or N;
[0088] R.sup.7 is a bond or arylene;
[0089] R.sup.7 is optionally substituted with --OH, halogen,
--C(O)CH.sub.3, --NR.sup.10R.sup.11, or
--N.sup.+R.sup.10R.sup.11R.sup.12 (R.sup.13).sup.-;
[0090] R.sup.8 is H, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, or --NH.sub.2;
[0091] R.sup.9, R.sup.10, R.sup.11, and R.sup.12 independently H or
C.sub.1-C.sub.10 alkyl;
[0092] R.sup.13 is a halide, hydroxide, sulfate, tetrafluoroborate,
or phosphate; and
[0093] R.sup.14, R.sup.15 and R.sup.16 are independently H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl substituted with
--COOH, C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12 alkenyl
substituted with --COOH, --C(O)R.sup.17;
[0094] R.sup.17 is --OH, C.sub.1-C.sub.10 alkyl, or
C.sub.2-C.sub.12 alkenyl; and
[0095] R.sup.18 is H, C.sub.1-C.sub.6 alkyl, --OH,
--NR.sup.14R.sup.15, or
N.sup.+R.sup.14R.sup.15R.sup.16(R.sup.13).
[0096] Embodiments of the invention may comprise dosage unit forms
for buccal administration comprising (a) at least one peptide YY, a
peptide YY agonist, or a mixture thereof, and (b) a delivery agent
of the formula
##STR00006##
or a salt thereof, wherein
[0097] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are
independently H, --CN, --OH, --OCH.sub.3, or halogen, at least one
of R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 being --CN;
and
[0098] R.sup.6 is C.sub.1-C.sub.12 linear or branched alkylene,
alkenylene, arylene, alkyl(arylene) or aryl(alkylene).
[0099] Embodiments of the invention may comprise a delivery agent
selected from the group comprising the monosodium salt of
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, the monosodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the monosodium salt
of 8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, the monosodium
salt of 8-(2,6-dihydroxybenzoylamino)octanoic acid, the monosodium
salt of 8-(2-hydroxy-5-bromobenzoylamino)octanoic acid, the
monosodium salt 8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,
the monosodium salt of 8-(2-hydroxy-5-iodobenzoylamino)octanoic
acid, the monosodium salt of
8-(2-hydroxy-5-methylbenzoylamino)octanoic acid, the monosodium
salt of 8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid, the
monosodium salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic
acid, the monosodium salt of 8-(3-hydroxyphenoxy)octanoic acid, the
monosodium salt of 8-(4-hydroxyphenoxy)octanoic acid, the
monosodium salt of 6-(2-cyanophenoxy)hexanoic acid, the monosodium
salt of 8-(2-Hydroxyphenoxy)octyl-diethanolamine, disodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid, the disodium salt of
8-(4-hydroxyphenoxy)octanoate, the monosodium salt of
8-(4-hydroxyphenoxy)octanoate, the disodium salt of
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid, and the disodium
salt of 8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid.
[0100] Embodiments of the invention may comprise a delivery agent
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceutically
acceptable salt thereof, or N-(10-[2-hydroxybenzoyl]-amino)decanoic
acid or a pharmaceutically acceptable salt thereof.
[0101] Embodiments of the invention may comprise a peptide YY
agonist selected from the functional domain of PYY, active
fragments of PYY, derivatives of PYY, fragments of PYY, or analogs
of PYY. The peptide YY agonist may, e.g., be PYY[3-36].
[0102] Embodiments of the invention may comprise any dosage unit
form described above with an excipient, a diluent, a disintegrant,
a lubricant, a plasticizer, a colorant, a dosing vehicle, or any
combination thereof.
[0103] Embodiments of the invention may comprise dosage unit forms
in the form of, e.g., a tablet, a capsule, a particle, a powder, a
sachet, or a liquid.
[0104] Embodiments of the invention may comprise a dosing vehicle
which is a liquid selected from the group comprising, e.g., water,
aqueous propylene glycol, phosphate buffer, 1,2-propane diol,
ethanol, or any combination thereof.
[0105] Embodiments of the invention may comprise methods for
administering an effective amount of peptide YY, a peptide YY
agonist or a combination thereof, to a patient in need thereof,
comprising the step of buccally administering any of the dosage
unit forms described above. The peptide YY agonist may be, e.g.,
PYY[3-36] and the delivery agent may be, e.g.,
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid or
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid or a pharmaceutically
acceptable salt thereof.
[0106] Embodiments of the invention may comprise methods of
treating obesity in a patient in need thereof, comprising the step
of administering to the patient an effective amount of any of the
dosage unit forms described above.
[0107] Embodiments of the invention may comprise methods of
treating a condition or disorder that may be alleviated by reducing
nutrient availability in a patient in need thereof, comprising the
step of administering to an animal an effective amount of any of
the dosage unit forms described above. The condition or disorder
may, e.g., be selected from the group comprising hypertension,
dyslipidemia, cardiovascular risk, an eating disorder,
insulin-resistance, obesity diabetes mellitus, cancer, cachexia and
malnutrition, or any combination thereof.
[0108] Embodiments of the invention may comprise methods of
reducing nutrient uptake in a patient in need thereof, comprising
the step of administering an effective amount of any of the dosage
unit forms described above.
[0109] Embodiments of the invention may comprise methods of
improving the lipid profile in a patient in need thereof,
comprising the step of administering an effective amount of any of
the dosage unit forms described above.
[0110] Embodiments of the invention may comprise methods of
improving the bioavailability of peptide YY or a peptide YY agonist
in an animal, the method comprising the step of administering any
of the dosage unit forms described above.
[0111] Embodiments of the invention may comprise methods of
preparing a dosage unit form comprising the step of mixing at least
one of a peptide YY and a peptide YY agonist, and a delivery agent
of the formula
##STR00007##
or a salt thereof, wherein:
[0112] Ar is phenyl or naphthyl;
[0113] Ar is optionally substituted with one or more of --OH,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4 haloalkoxy;
[0114] R.sup.7 is selected from C.sub.4-C.sub.20 alkyl,
C.sub.4-C.sub.20 alkenyl, phenyl, naphthyl, (C.sub.1-C.sub.10
alkyl) phenyl, (C.sub.1-C.sub.10 alkenyl)phenyl, (C.sub.1-C.sub.10
alkyl) naphthyl, (C.sub.1-C.sub.10 alkenyl) naphthyl,
phenyl(C.sub.1-C.sub.10 alkyl), phenyl(C.sub.1-C.sub.10 alkenyl),
naphthyl(C.sub.1-C.sub.10 alkyl), or naphthyl(C.sub.1-C.sub.10
alkenyl);
[0115] R.sup.8 is selected from hydrogen, C.sub.1 to C.sub.4 alkyl,
C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, and
C.sub.1-C.sub.4 haloalkoxy;
[0116] R.sup.7 is optionally substituted with C.sub.1 to C.sub.4
alkyl, C.sub.2 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --OH, --SH, and --CO.sub.2R.sup.9, or
any combination thereof;
[0117] R.sup.9 is hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.2 to
C.sub.4 alkenyl; and
[0118] R.sup.7 is optionally interrupted by oxygen, nitrogen,
sulfur or any combination thereof.
Definitions
[0119] The term "hydrate" as used herein includes, but is not
limited to, (i) a substance containing water combined in the
molecular form and (ii) a crystalline substance containing one or
more molecules of water of crystallization or a crystalline
material containing free water.
[0120] The term "solvate" as used herein includes, but is not
limited to, a molecular or ionic complex of molecules or ions of a
solvent with molecules or ions of the delivery agent compound or
salt thereof, or hydrate or solvate thereof.
[0121] The term "delivery agent" refers to any of the delivery
agent compounds disclosed herein.
[0122] The term "SNAC" refers to the monosodium salt of
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid.
[0123] The term "SNAD" refers to the monosodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid. The term "disodium
salt of SNAD" refers to the disodium salt of
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid.
[0124] An "effective amount of PYY, PYY agonist, or a mixture
thereof" is an amount of the PYY, the PYY agonist, or mixture
thereof which is effective to treat or prevent a condition in a
living organism to whom it is administered over some period of
time, e.g., provides a therapeutic effect during a desired dosing
interval.
[0125] An "effective amount of delivery agent" is an amount of the
delivery agent which enables and/or facilitates the absorption of a
desired amount of PYY or PYY agonist via any route of
administration (such as those discussed in this application
including, but not limited to, the oral (e.g., across a biological
membrane in the gastrointestinal tract), nasal, pulmonary, dermal,
buccal, vaginal, and/or ocular route).
[0126] The term "AUC" as used herein, means area under the plasma
concentration-time curve, as calculated by the trapezoidal rule
over the complete dosing interval, e.g., 24-hour interval.
[0127] The term "mean", when preceding a pharmacokinetic value
(e.g., mean Peak) represents the arithmetic mean value of the
pharmacokinetic value unless otherwise specified.
[0128] As used herein and in the appended claims, the singular
forms "a," "an," and "the," include plural referents unless the
context clearly indicates otherwise. Thus, for example, reference
to "a molecule" includes one or more of such molecules, "a reagent"
includes one or more of such different reagents, reference to "an
antibody" includes one or more of such different antibodies, and
reference to "the method" includes reference to equivalent steps
and methods known to those of ordinary skill in the art that could
be modified or substituted for the methods described herein.
[0129] The term "about" generally means within 10%, preferably
within 5%, and more preferably within 1% of a given value or
range.
[0130] The terms "alkyl" and "alkenyl" as used herein include
linear and branched alkyl and alkenyl substituents,
respectively.
[0131] The term "patient" as used herein refers to a mammal and
preferably a human.
[0132] The phrase "pharmaceutically acceptable" refers to additives
or compositions that are physiologically tolerable when
administered to a mammal.
[0133] The terms "buccal administration" and "buccally
administering" include administration by adsorption through any
surface inside the mouth or upper throat (such as the cheek (e.g.,
the inner cheek lining), gums, palate, tongue, tonsils, periodontal
tissue, lips, and the mucosa of the mouth and pharynx). These
terms, for example, include sublingual and intraoral
administration.
PYY and PYY Agonists
[0134] By "peptide YY" or "PYY" is meant a Peptide YY polypeptide
obtained or derived from any species. Thus, the term "PYY" includes
both the human full length, 36 amino acid peptide as set forth in
SEQ ID NO: 2 of International Publication No. WO 02/47712 (which is
the PCT counterpart to U.S. Patent Publication No. 2002/0141985,
which is hereby incorporated by reference) and Tatemoto, Proc Natl
Acad Sci U.S.A. 79:2514-8, 1982, and species variations of PYY,
including e.g., murine, hamster, chicken, bovine, rat, and dog PYY,
for example. By "PYY agonist" is meant any compound which elicits
an effect of PYY to reduce nutrient availability, for example a
compound (1) having activity in the food intake, gastric emptying,
pancreatic secretion, or weight loss assays described in Examples
1, 2, 5, or 6 of WO 02/47712 and U.S. Patent Publication No.
2002/0141985, and (2) which binds specifically in a Y receptor
assay (Example 10 of WO 02/47712 and U.S. Patent Publication No.
2002/0141985) or in a competitive binding assay with labeled PYY or
PYY [3-36] from certain tissues having an abundance of Y receptors,
including e.g., area postrema (Example 9 of WO 02/47712 and U.S.
Patent Publication No. 2002/0141985), wherein the PYY agonist is
not pancreatic polypeptide. Preferably, PYY agonists would bind in
such assays with an affinity of greater than about 1 .mu.M, and
more preferably with an affinity of greater than about 1 to about 5
nM.
[0135] Such agonists can comprise a polypeptide having a functional
PYY domain, an active fragment of PYY, or a chemical or small
molecule. PYY agonists may be peptide or nonpeptide compounds, and
include "PYY agonist analogs," which refer to any compound
structurally similar to a PYY that have PYY activity typically by
virtue of binding to or otherwise directly or indirectly
interacting with a PYY receptor or other receptor or receptors with
which PYY itself may interact to elicit a biological response. Such
compounds include derivatives of PYY, fragments of PYY, extended
PYY molecules having more than 36 amino acids, truncated PYY
molecules having less than 36 amino acids, and substituted PYY
molecules having one or more different amino acids, or any
combination of the above. Such compounds may also be modified by
processes such as pegylation, amidation, glycosylation, acylation,
sulfation, phosphorylation, acetylation and cyclization.
[0136] One such PYY agonist analog is PYY [3-36], identified as SEQ
ID NO: 3 of WO 02/47712 and U.S. Patent Publication No.
2002/0141985; Eberlein, Eysselein et al., Peptides 10:797-803
(1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994).
Polypeptides with numbers in brackets refer to truncated
polypeptides having the sequence of the full length peptide over
the amino acid positions in the brackets. Thus, PYY [3-36] has a
sequence identical to PYY over amino acids 3 to 36. PYY[3-36]
contains approximately 40% of total peptide YY-like
immunoreactivity in human and canine intestinal extracts and about
36% of total plasma peptide YY immunoreactivity in a fasting state
to slightly over 50% following a meal. It is apparently a
dipeptidyl peptidase-IV (DPP4) cleavage product of peptide YY.
Peptide YY[3-36] is reportedly a selective ligand at the Y2 and Y5
receptors, which appear pharmacologically unique in preferring
N-terminally truncated (i.e. C terminal fragments of) neuropeptide
Y analogs. A PYY agonist may bind to a PYY receptor with higher or
lower affinity, demonstrate a longer or shorter half-life in vivo
or in vitro, or be more or less effective than native PYY.
[0137] Other suitable PYY agonists include those described in
International Publication No. WO 98/20885, which is hereby
incorporated by reference.
[0138] By "condition or disorder which can be alleviated by
reducing caloric (or nutrient) availability" is meant any condition
or disorder in an animal that is either caused by, complicated by,
or aggravated by a relatively high nutrient availability, or that
can be alleviated by reducing nutrient availability, for example by
decreasing food intake. Such conditions or disorders include, but
are not limited to, obesity, diabetes, including type 2 diabetes,
eating disorders, and insulin-resistance syndromes.
[0139] In one aspect, the invention provides a method of treating
obesity in an obese or overweight animal by administering a
therapeutically effective amount of PYY, a PYY agonist, or a
mixture thereof with at least one delivery agent compound. While
"obesity" is generally defined as a body mass index over 30, for
purposes of this disclosure, any subject, including those with a
body mass index of less than 30, who needs or wishes to reduce body
weight is included in the scope of "obese." Subjects who are
insulin resistant, glucose intolerant, or have any form of diabetes
mellitus (e. g., type 1, 2 or gestational diabetes) can benefit
from this method.
[0140] In other aspects, the invention features methods of reducing
food intake, treating diabetes mellitus, and improving lipid
profile (including reducing LDL, HDL, VLDL, total cholesterol
and/or triglyceride levels) comprising administering to a subject a
therapeutically effective amount of PYY, a PYY agonist, or a
mixture thereof with at least one delivery agent compound. In a
preferred embodiment, the methods of the invention are used to
treat conditions or disorders which can be alleviated by reducing
nutrient availability in a subject in need thereof, comprising
administering to said subject a therapeutically effective amount of
PYY, a PYY agonist, or a mixture thereof with at least one delivery
agent compound. Such conditions and disorders include, but are not
limited to, hypertension, dyslipidemia, cardiovascular disease,
eating disorders, insulin-resistance, obesity, and diabetes
mellitus of any kind.
[0141] In the methods of the invention, preferred PYY agonists are
those having a potency in one of the assays described in WO
02/47712 and U.S. Patent Publication No. 2002/0141985 (preferably
food intake, gastric emptying, pancreatic secretion, or weight
reduction assays) which is greater than the potency of NPY
(Neuropeptide Y) in that same assay.
[0142] In one embodiment, for treatment of all conditions and
disorders described herein, a preferred PYY agonist is PYY [3-36],
and is administered (e.g. peripherally) at a dose of about 1 pg to
about 5 mg per day in single or divided doses. Alternatively
PYY[3-36] may be administered on the basis of the recipients total
body weight in an amount of about 0.01 .mu.g/kg to about 500
.mu.g/kg, or about 0.05 .mu.g/kg to about 250 .mu.g/kg, or less
than about 50 .mu.g/kg, per day in a single or divided doses.
Dosages in these ranges will vary with the potency of each agonist,
of course, and are readily determined by one of skill in the
art.
[0143] In the methods of the present invention, PYY's and PYY
agonists with the delivery agent compound may be administered
separately or together with one or more other compounds and
compositions that exhibit a long term or short-term action to
reduce nutrient availability, including, but not limited to other
compounds and compositions that comprise an amylin or amylin
agonist, a cholecystokinin (CCK) or CCK agonist, a leptin (OB
protein) or leptin agonist, an exendin or exendin agonist, or a
GLP-1 or GLP-1 agonist. Suitable amylin agonists include, for
example, [25,28,29Pro-]-human amylin (also known as "pramlintide",
and described in U.S. Pat. Nos. 5,686,511 and 5,998,367),
calcitonin (e.g., salmon calcitonin), including those described in
U.S. Pat. No. 5,739,106, which is hereby incorporated by reference.
The CCK used is preferably CCK octopeptide (CCK-8). Leptin is
discussed in, for example, Pelleymounter, C. et al., Science 269:
540-543 (1995), Halaas, G. et al., Science 269: 543-6 (1995) and
Campfield, S. et al., Science 269: 546-549 (1995). Suitable CCK
agonist includes those described in U.S. Pat. No. 5,739,106, which
is hereby incorporated by reference. Suitable exendins include
exendin-3 and exendin-4, and exendin agonist compounds include, for
example, those described in PCT Publications WO 99/07404, WO
99/25727, and WO 99/25728, all of which are hereby incorporated by
reference. According to one embodiment, the composition of the
present invention includes at least one delivery agent compound,
PYY, a PYY agonist, or a mixture thereof, at least one amylin
agonist, and a CCK agonist. Suitable combinations of amylin agonist
and CCK agonist include, but are not limited to, those described in
U.S. Pat. No. 5,739,106, which is hereby incorporated by
reference.
[0144] PYY and PYY[3-36] are C-terminally amidated when expressed
physiologically, but need not be for the purposes of the present
invention. These peptides may also have other posttranslational
modifications.
[0145] PYY and peptide-based PYY agonists described herein may be
prepared using standard recombinant expression or chemical peptide
synthesis techniques known in the art, e. g., using an automated or
semiautomated peptide synthesizer. PYY as described herein include
any morphologies of PYY [3-36], including those obtained by
lyophilization, crystallization, reconstitution, spray drying, and
super critical fluid processing.
[0146] Solid phase peptide synthesis may be carried out with an
automatic peptide synthesizer (e. g., Model 430A, Applied
Biosystems Inc., Foster City, Calif.) using the NMP/HOBt (Option 1)
system and tBoc or Fmoc chemistry (see, Applied Biosystems User's
Manual for the ABI 430A Peptide Synthesizer, Version 1.3B Jul. 1,
1988, 6: 4970, Applied Biosystems, Inc., Foster City, Calif.) with
capping. Peptides may be also be assembled using an Advanced Chem
Tech Synthesizer (Model MPS 350, Louisville, Ky.). Peptides may be
purified by RP-HPLC (preparative and analytical) using, e.g., a
Waters Delta Prep 3000 system and a C4, C8 or C18 preparative
column (10 p, 2.2.times.25 cm; Vydac, Hesperia, Calif.).
[0147] Peptide compounds useful in the invention may also be
prepared using recombinant DNA techniques, using methods now known
in the art. See, e. g., Sambrook et al., Molecular Cloning: A
Laboratory Manual, 2d Ed., Cold Spring Harbor (1989). Non-peptide
compounds useful in the present invention may be prepared by
art-known methods. For example, phosphate-containing amino acids
and peptides containing such amino acids, may be prepared using
methods known in the art. See, e. g., Bartlett and Landen, Biorg
Chem. 14: 356-377 (1986).
[0148] The compositions useful in the invention can be provided as
parenteral compositions for e. g., injection or infusion. For
example, they may be suspended in an aqueous carrier, for example,
in an isotonic buffer solution at a pH of about 3.0 to about 8.0.
Useful buffers include sodium citrate-citric acid and sodium
phosphate-phosphoric acid, and sodium acetate/acetic acid buffers.
A form of repository or "depot" slow release preparation may be
used so that therapeutically effective amounts of the preparation
are delivered into the bloodstream over many hours or days
following transdermal injection or delivery.
[0149] Since PYY and many PYY agonists are amphoteric, they may be
utilized as free bases, as acid addition salts or as metal salts.
The salts preferably are pharmaceutically acceptable, and these
will include metal salts, particularly alkali and alkaline earth
metal salts, e.g., potassium or sodium salts. A wide variety of
pharmaceutically acceptable acid addition salts are available. Such
products are readily prepared by procedures well known to those
skilled in the art.
[0150] Therapeutically effective amounts of a PYY or a PYY agonist
for use in reducing nutrient availability are those that suppress
appetite at a desired level. As will be recognized by those in the
field, an effective amount of therapeutic agent will vary with many
factors including the age and weight of the patient, the patient's
physical condition, the blood sugar level, the weight level to be
obtained, and other factors.
[0151] The effective daily appetite-suppressing dose of PYY, a PYY
agonist, or a mixture thereof may be in the range of about 1 to 30
.mu.g to about 50 mg/day, or about 10 to 30 .mu.g to about 20
mg/day and or about 5 to 100 .mu.g to about 10 mg/day, or about 5
.mu.g to about 5 mg/day, for a 50 kg patient. Effective amounts of
PYY or a PYY agonist may be administered in a single or divided
doses. The dosages may be between about 0.01 to about 1 mg/kg/dose.
The exact dose to be administered may be determined by one of skill
in the art and is dependent upon the potency of PYY, PYY agonist,
or mixture thereof, as well as upon the age, weight and condition
of the individual. Administration should begin whenever the
suppression of nutrient availability, food intake, weight, blood
glucose or plasma lipid lowering is desired, for example, at the
first sign of symptoms or shortly after diagnosis of obesity,
diabetes mellitus, or insulin resistance syndrome.
Screening for Additional PYY Agonists
[0152] Other PYY agonists can be identified by using the receptor
binding assays described below (e. g., in Examples 9 and 10 of WO
02/47712 and U.S. Patent Publication No. 2002/0141985) or known in
the art in combination with the physiological screens described in
the examples in WO 02/47712 and U.S. Patent Publication No.
2002/0141985. Potential PYY agonists can be compared with the
activity of PYY or PYY [3-36].
[0153] Alternatively, once one or more PYY-preferring (Y7)
receptors have been characterized and cloned, alternative assays
and high throughput screens can be implemented as discussed below
or known in the art. Y7 receptors are those with an affinity for
PYY or PYY [3-36] greater than their affinity for neuropeptide Y
(NPY). Methods of screening for compounds which modulate PYY
receptor activity comprise contacting test compounds with PYY
receptors and assaying for the presence of a complex between the
compound and the PYY receptors. In such assays, the test ligand is
typically labeled. After suitable incubation, free ligand is
separated from that present in bound form, and the amount of free
or uncomplexed label is a measure of the ability of the particular
compound to bind to the PYY receptors.
[0154] Alternatively, bound labeled ligand may be measured (e. g.,
using expressed membrane bound Y7 receptors).
[0155] High throughput screening for PYY agonists having suitable
binding affinity to PYY receptors may be employed. For example,
large numbers of different small peptide test compounds are
synthesized on a solid substrate. The peptide test compounds are
contacted with the PYY receptor and washed. Bound PYY receptor is
then detected by methods well known in the art. Purified test
compounds can also be coated directly onto plates for use in the
aforementioned drug screening techniques. In addition, if the test
compounds are proteins, antibodies can be used to capture the
protein and immobilize it on the solid support by any means known
in the art.
[0156] Competitive screening assays may be used in which
neutralizing antibodies capable of binding a polypeptide of the
invention specifically compete with a test compound for binding to
the polypeptide. In this manner, the antibodies can be used to
detect the presence of any peptide that shares one or more
antigenic determinants with a PYY agonist. Radiolabeled competitive
binding studies are described in Lin, A. H. et al., Antimicrobial
Agents and Chemotherapy 41(10): 2127-2131 (1997), the disclosure of
which is incorporated herein by reference in its entirety.
Delivery Agent Compounds
[0157] The delivery agent compound may be any of those described in
U.S. Pat. Nos. 5,650,386 and 5,866,536 and International
Publication Nos. WO94/23767, WO95/11690, W095/28920, WO95/28838,
W096/10396, W096/09813, WO96/12473, WO96/12475, WO96/30036,
WO96/33699, WO97/31938, WO97/36480, WO98/21951, WO98/25589,
W098/34632, W098/49135, WO99/16427, WO00/06534, WO00/07979,
WO00/40203, WO00/46182, WO00/47188, WO00/48589, WO00/50386,
WO00/59863, WO00/59480, WO01/32130, WO01/32596, WO01/34114,
WO01/44199, WO01/51454, WO01/70219, WO01/92206, WO02/02509,
WO02/15959, WO02/16309, WO02/20466, WO02/19969, WO02/070438,
WO03/026582, WO02/100338, WO03/045306, and WO0326582, all of which
are hereby incorporated by reference.
[0158] Non-limiting examples of delivery agent compounds include
N-(8-[2-hydroxybenzoyl]-amino)caprylic acid,
N-(10-[2-hydroxybenzoyl]-amino)decanoic acid,
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,
8-(2,6-dihydroxybenzoylamino)octanoic acid,
8-(2-hydroxy-5-bromobenzoylamino)octanoic acid,
8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-iodobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methylbenzoylamino)octanoic acid,
8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid,
8-(3-hydroxyphenoxy)octanoic acid, 8-(4-hydroxyphenoxy)octanoic
acid, 6-(2-cyanophenoxy)hexanoic acid,
8-(2-Hydroxyphenoxy)octyl-diethanolamine,
8-(4-hydroxyphenoxy)octanoate, 8-(4-hydroxyphenoxy)octanoate,
8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,
8-(2-hydroxy-5-methoxybenzoylamino)-octanoic acid., and salts
thereof. Preferred salts include, but are not limited to,
monosodium and disodium salts.
[0159] The delivery agent compounds may be in the form of the
carboxylic acid or pharmaceutically acceptable salts thereof, such
as sodium salts, and hydrates and solvates thereof. The salts may
be mono- or multi-valent salts, such as monosodium salts and
disodium salts. The delivery agent compounds may contain different
counter ions chosen for example due to their effect on modifying
the dissolution profile of the carrier.
[0160] The delivery agent compounds may be prepared by methods
known in the art, such as those discussed in the aforementioned
publications (e.g., International Publication Nos. WO 98/34632, WO
00/07979, WO 01/44199, WO 01/32596, WO 02/20466, and WO 03/045306).
SNAC, SNAD, and the free acid and other salts thereof may be
prepared by any method known in the art, such as those described in
U.S. Pat. Nos. 5,650,386 and 5,866,536.
[0161] Salts of the delivery agent compounds of the present
invention may be prepared by methods known in the art. For example,
sodium salts may be prepared by dissolving the delivery agent
compound in ethanol and adding aqueous sodium hydroxide.
[0162] The delivery agent compound may be purified by
recrystallization or by fractionation on one or more solid
chromatographic supports, alone or linked in tandem. Suitable
recrystallization solvent systems include, but are not limited to,
acetonitrile, methanol, and tetrahydrofuran. Fractionation may be
performed on a suitable chromatographic support such as alumina,
using methanol/n-propanol mixtures as the mobile phase; reverse
phase chromatography using trifluoroacetic acid/acetonitrile
mixtures as the mobile phase; and ion exchange chromatography using
water or an appropriate buffer as the mobile phase. When anion
exchange chromatography is performed, preferably a 0-500 mM sodium
chloride gradient is employed.
Delivery Systems
[0163] The composition of the present invention comprises one or
more delivery agent compounds of the present invention and/or one
or more of PYY and PYY agonists. The delivery agent compound and
PYY and/or the PYY agonists are typically mixed prior to
administration to form an administration composition.
[0164] The composition may include one or more
food-intake-reducing, plasma glucose-lowering or plasma
lipid-altering agents, such as an amylin, an amylin agonist, a CCK,
or CCK agonist, or a leptin or leptin agonist, or an exendin or
exendin agonist.
[0165] The administration compositions may be in the form of a
liquid. The solution medium may comprise dosing vehicles such as,
e.g., water, 25% aqueous propylene glycol, or phosphate buffer.
Other dosing vehicles include polyethylene glycol. Dosing solutions
may be prepared by mixing a solution of the delivery agent compound
with a solution of the active agent, just prior to administration.
Alternately, a solution of the delivery agent compound (or PYY, PYY
agonist, or mixture thereof) may be mixed with the solid form of
PYY or the PYY agonist (or delivery agent compound). The delivery
agent compound and PYY, PYY agonist, or mixture thereof may also be
mixed as dry powders. The delivery agent compound and PYY, PYY
agonist, or mixture thereof can also be admixed during the
manufacturing process.
[0166] The dosing solutions may optionally contain additives such
as phosphate buffer salts, citric acid, glycols, or other
dispersing agents. Stabilizing additives may be incorporated into
the solution, preferably at a concentration ranging between about
0.1 and 20% (w/v).
[0167] The administration compositions may alternately be in the
form of a solid, such as a tablet, capsule or particle, such as a
powder or sachet. Solid dosage forms may be prepared by mixing the
solid form of the compound with the solid form of PYY, PYY agonist,
or mixture thereof. Alternately, a solid may be obtained from a
solution of compound and PYY, PYY agonist, or mixture thereof by
methods known in the art, such as freeze-drying (lyophilization),
precipitation, crystallization and solid dispersion. Alternatively,
the administration can be a semi-solid, in the form of a gel,
paste, colloid, gelatin, emulsion, suspension and the like.
[0168] The administration compositions of the present invention may
also include one or more enzyme inhibitors. Such enzyme inhibitors
include, but are not limited to, compounds such as actinonin or
epiactinonin and derivatives thereof. Other enzyme inhibitors
include, but are not limited to, aprotinin (Trasylol) and
Bowman-Birk inhibitor.
[0169] The amount of PYY and/or the PYY agonist used in an
administration composition of the present invention is an amount
effective to treat the target indication. However, the amount can
be less than that amount when the composition is used in a dosage
unit form because the dosage unit form may contain a plurality of
delivery agent compound/PYY or the PYY agonist compositions or may
contain a divided effective amount. The total effective amount can
then be administered in cumulative units containing, in total, an
effective amount of PYY, PYY agonist, or mixture thereof. Moreover,
those skilled in the filed will recognize that an effective amount
of PYY, PYY agonist, or mixture thereof will vary with many factors
including the age and weight of the patient, the patient's physical
condition, the blood sugar level, the weight level to be obtained,
as well as other factors.
[0170] The total amount to be used of PYY or the PYY agonist can be
determined by methods known to those skilled in the art. However,
because the compositions of the invention may deliver PYY or the
PYY agonist more efficiently than compositions containing PYY or
the PYY agonist alone, lower amounts of PYY or the PYY agonist than
those used in prior dosage unit forms or delivery systems can be
administered to the subject, while still achieving the same blood
levels and/or therapeutic effects.
[0171] According to one embodiment the amount of PYY, PYY agonist,
or mixture thereof administered with the delivery agent is an
amount sufficient to suppress appetite to a desired level. The
effective daily appetite-suppressing dose of PYY, a PYY agonist, or
a mixture thereof generally ranges from about 1 .mu.g about 5 mg
per day in single or divided doses, preferably from about 5 .mu.g
to about 2 mg/day, and more preferably from about 5 .mu.g to 500
.mu.g/day for a 50 kg patient. Preferably the dosage forms of the
present invention consist from about 0.01 and about 10
.mu.g/kg/dose of PYY, a PYY agonist, or a mixture thereof.
[0172] The present invention also includes pharmaceutical
compositions and dosage forms which include the aforementioned
amounts of PYY, a PYY agonist, or a mixture thereof and at least
one delivery agent
[0173] Generally an effective amount of delivery agent to
facilitate the delivery of PYY and/or the PYY agonist is
administered with PYY, PYY agonist, or a mixture thereof. Generally
the amount of delivery agent to PYY, PYY agonist, or mixture
thereof, on a molar basis ranges from about 25000:1 to about 50:1,
preferably from about 8000:1 to about 100:1 and most preferably
from about 4000:1 to about 300:1. It is envisioned that ratios
smaller than about 50:1, possibly as small as about 1:1, or less
than about 1:1, may be efficacious in some circumstances.
[0174] The presently disclosed delivery agent compounds facilitate
the delivery of PYY, a PYY agonist, or a mixture thereof,
particularly in oral, intranasal, sublingual, intraduodenal,
subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal,
pulmonary, transdermal, intradermal, parenteral, intraperitoneal,
intravenous, intramuscular and ocular systems, as well as
traversing the blood-brain barrier. The compositions and dosage
unit forms of the present invention may be administered by any of
the aforementioned routes.
[0175] The compositions and dosage unit form of the present
invention when administered orally or buccally to a human may
achieve known therapeutic levels of PYY[3-36] in the body, such as
those enumerated in Batterham et al., Nature 418:650-654(2002).
[0176] Without being bound by any particular theory, applicants
believe that the compositions of the present invention may be
administered buccally, and that there is less dilution and fewer
food effects when PYY or PYY agonist is absorbed buccally. Buccal
administration can also provide a sustained (flat) release profile,
which is helpful, for example, to prevent subjects from eating over
a longer time period.
[0177] Dosage unit forms can also include any one or combination of
excipients, diluents, disintegrants, lubricants, plasticizers,
colorants, flavorants, taste-masking agents, sugars, sweeteners,
salts, and dosing vehicles, including, but not limited to, water,
1,2-propane diol, ethanol, olive oil, or any combination
thereof.
[0178] Dosage unit forms for buccal administrations may contain
ingredients known to facilitate buccal administration. The buccal
dosage unit form, for example, may be formulated so as to erode
gradually over a predetermined time period and release the PYY or
PYY agonist and delivery agent at a constant or substantially
constant rate. According to one embodiment, the time period ranges
from about 0.5 hours to about 24 hours. A bioerodible
(hydrolyzable) polymeric carrier that adheres the dosage form to
the buccal mucosa, such as that described in U.S. Published Patent
Application No. 2003/0134861 (which is hereby incorporated by
reference), can be used, e.g., to provide a sustained release
profile. Suitable bioerodible (hydrolyzable) polymeric carriers
include, but are not limited to, those which provide a sustained
release profile and are compatible with the PYY or PYY agonist and
delivery agent. According to one embodiment, the polymeric carrier
comprises hydrophilic (water-soluble and water-swellable) polymers
that adhere to the wet surface of the buccal mucosa. Non-limiting
examples of polymeric carriers useful herein include acrylic acid
polymers, e.g., those known as "carbomers" (Carbopol.RTM., which
may be obtained from B. F. Goodrich is one such polymer). Other
suitable polymers include, but are not limited to: hydrolyzed
polyvinylalcohol; polyethylene oxides (e.g., Sentry Polyox.RTM.
water soluble resins, available from Union Carbide of Midland,
Mich.); polyacrylates (e.g., Gantrez.RTM., which may be obtained
from GAF of Wayne, N.J.); vinyl polymers and copolymers;
polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and
cellulosic polymers such as hydroxypropyl methylcellulose (e.g.,
Methocel.RTM., which may be obtained from the Dow Chemical Company
of Midland, Mich.), hydroxypropyl cellulose (e.g., Klucel.RTM.,
which may also be obtained from Dow), hydroxypropyl cellulose
ethers (see, e.g., U.S. Pat. No. 4,704,285 to Alderman),
hydroxyethyl cellulose, carboxymethyl cellulose, sodium
carboxymethyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate phthalate, cellulose acetate butyrate, and the
like.
[0179] Other components may also be incorporated into the buccal
dosage forms described herein. The additional components include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like.
Non-limiting examples of disintegrants are manitol, sodium starch
glycolate, cross-linked polyvinylpyrrolidones, such as crospovidone
(e.g., Polyplasdone.RTM. XL, which may be obtained from GAF),
cross-linked carboxylic methylcelluloses, such as croscarmelose
(e.g., Ac-di-sol.RTM., which may be obtained from FMC Corporation
of Philadelphia, Pa.), alginic acid, and sodium carboxymethyl
starches (e.g., Explotab.RTM., which may be obtained from Edward
Medell Co., Inc.), methylcellulose, agar bentonite and alginic
acid. Suitable diluents include, but are not limited to, those
which are generally useful in pharmaceutical formulations prepared
using compression techniques, e.g., dicalcium phosphate dihydrate
(e.g., Di-Tab.RTM., which may be obtained from Stauffer), sugars
that have been processed by cocrystallization with dextrin (e.g.,
co-crystallized sucrose and dextrin such as Di-Pakg, which may be
obtained from Amstar), lactone, calcium phosphate, cellulose,
kaolin, mannitol, sodium chloride, dry starch, powdered sugar and
the like. Suitable binders include, but are not limited to, those
that enhance adhesion. Non-limiting examples of such binders are
starch, gelatin and sugars such as sucrose, dextrose, molasses, and
lactose. Non-limiting examples of lubricants include, but are not
limited to, stearates (e.g., magnesium stearate) and stearic
acid.
[0180] Preferred sublingual dosage forms include sublingual
tablets, creams, ointments and pastes. The tablet, cream, ointment
or paste for sublingual delivery comprises a therapeutically
effective amount of PYY or PYY agonist and one or more conventional
nontoxic carriers suitable for sublingual drug administration. The
sublingual dosage forms of the present invention can be
manufactured using conventional processes. The sublingual dosage
unit is fabricated to disintegrate rapidly. The time period for
complete disintegration of the dosage unit is typically in the
range of from about 10 seconds to about 30 minutes, and optimally
is less than 5 minutes.
[0181] Other components may also be incorporated into the
sublingual dosage forms described herein. The additional components
include, but are not limited to, binders, disintegrators, wetting
agents, lubricants, and the like. Examples of binders that may be
used include water, ethanol, polyvinyl pyrrolidone, and starch
solution gelatin solution. Suitable disintegrators include, but are
not limited to, dry starch, calcium carbonate, polyoxyethylene
sorbitan fatty acid esters, sodium lauryl sulfate, stearic
monoglyceride, and lactose. Wetting agents, if used, include
glycerin, and starches. Suitable lubricants include but are not
limited to, stearates and polyethylene glycol. Additional
components that may be incorporated into sublingual dosage forms
include those known in the art; such as those described in
Remington's, The Science and Practice of Pharmacy, (Gennaro, A. R.,
ed., 20th edition, 2003, Mack Pub. Co.) which is herein
incorporated by reference.
[0182] One or more of a solvent, an optional cosolvent, a hydrogel,
and an oral mucosal membrane transport enhancing agent, such as
those described in U.S. Pat. No. 5,284,657 (which is hereby
incorporated by reference), may be included in the dosage unit form
for buccal administration. The solvent may comprise from about 50
percent w/v to about 95 percent w/v or from about 55 percent w/v to
about 80 percent w/v of a carrier of a non-toxic alcohol. Suitable
non-toxic alcohols include, but are not limited to, ethanol,
isopropanol, stearyl alcohol, propylene glycol, and polyethylene
glycol (e.g., those having a molecular weight of up to about 650
daltons). Non-toxic alcohols for use in pharmaceutical formulations
are well known in the art (cf., for example, Handbook of
Pharmaceutical Excipients, published by the American Pharmaceutical
Association and The Pharmaceutical Society of Great Britain (1986),
which is hereby incorporated by reference in its entirety).
[0183] The cosolvent may be selected from water or a
pharmaceutically acceptable oil. Suitable oils for use in the unit
dosage form of this invention include mineral oil, Neobee.TM. oil,
olive oil, sunflower oil, corn oil, peanut oil and the like.
Hydrogels suitable for use in the dosage unit form include
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium
carboxymethylcellulose (CMC), polyacrylic acid, and poly(methyl
methacrylic acid).
[0184] Typically, the oral mucosal membrane transport enhancing
agent facilitates the absorption of the therapeutic agent (e.g.,
PYY or PYY agonist) across the mucosal tissues in the oral cavity
and directly into the blood stream of the subject. Suitable tissue
transport enhancing agents include, but are not limited to,
pharmaceutically acceptable and non-toxic essential oils, volatile
oils, inorganic acids, and organic acids.
[0185] Essential or volatile oils which may be employed in the
compositions include, but are not limited to, peppermint oil,
spearmint oil, menthol, pepper oil, eucalyptus oil, cinnamon oil,
ginger oil, fennel oil, and dill oil. The essential or volatile
oil, when employed as the oral mucosal membrane transport enhancing
agent in the dosage unit form may be present in a concentration
ranging between about 0.5 percent w/v and about 50 percent w/v of
the carrier.
[0186] Suitable inorganic and organic acids include, but are not
limited to, hydrochloric acid, phosphoric acid, aromatic and
aliphatic monocarboxylic or dicarboxylic acids of from two to
thirty carbon atoms such as acetic acid, citric acid, lactic acid,
oleic acid, linoleic acid, lauric acid, plamitic acid, benzoic
acid, and salicylic acid. As used in this paragraph, the term
"aromatic" carboxylic acid refers to any acid which contains the
6-membered carbocyclic ring system characteristic of benzene, and
the term "aliphatic" carboxylic acid refers to any acid which
contains a straight-chain or branched chain saturated or
unsaturated hydrocarbon backbone.
[0187] Liquid compositions for buccal administration can be
formulated into a liquid spray, a liquid drop, a gel or a paste.
The desired consistency can be achieved by including in the liquid
composition one or more hydrogels, substances that absorb water and
produce gels of varying viscosity. Hydrogels suitable for use in
pharmaceutical preparations include those known well known in the
art, such as those described in Handbook of Pharmaceutical
Excipients, supra, and Handbook of Water-Soluble Gums and Resins,
ed. by R. L. Davidson, McGraw-Hill Book Co., New York, N.Y. (1980)
(both of which are hereby incorporated by reference).
[0188] Suitable hydrogels for use in the compositions of this
invention include hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, sodium carboxymethyl cellulose, polyacrylic acid,
poly(methyl methacrylic acid) (PMMA). Preferred hydrogels are
cellulose ethers such as hydroxyalkylcellulose (e.g., hydroxypropyl
cellulose) and hydroxyalkylalkyl-cellulose compounds. Hydroxypropyl
cellulose is commercially available in a wide range of viscosity
grades sold under the tradename Klucel.TM. (Hercules, Ltd., London,
England). The concentration of the hydroxyalkylcellulose is
dependent upon the particular viscosity grade used and the desired
viscosity of the liquid composition. For example, where the desired
viscosity is less than about 1000 centipoise (cps), hydroxypropyl
cellulose having an average molecular weight of about 60,000
daltons (i. e., Klucel EF.TM.) can be used. Where the desired
viscosity is from about 1000 to about 2500 cps, higher viscosity
grades of hydroxypropyl cellulose can be used (e.g., Klucel LF.TM.
and Lucel GF.TM.).
[0189] The dosage unit form for buccal administration may also
include collagen, a water soluble additive, and/or other
pharmaceutical additives, such as those described in U.S. Pat. No.
5,496,559. Collagen includes, for example, atelocollagen which is
derived from a natural resource, and which is free of a telopeptide
which is an antigenic portion of collagen; chemically modified
atelocollagen; and naturally-occurring collagen. The collagen which
has been chemically derived from the atelocollagen includes, for
example, a succinylated collagen and a methylated collagen. The
naturally-occurring collagen includes, for example, a collagen from
a skin of bovine, a chorda of bovine, a bowel of porcine and sheep,
and a human placenta. The collagen can contain a buffer, such as
phosphate buffer, citrate buffer, and acetate buffer, and/or a
stabilizer. Water soluble additives include for example, proteins,
glycoproteins, amino acids, polyamino acids, peptides, saccharides,
water-soluble polysaccharides, or a combination thereof. Proteins
include, for example, gelatin and albumin. Glycoproteins include,
for example, globulin. Amino acids include, for example, aspartic
acid, arginine, glycine, and leucine. Polyamino acids and peptides
include, for example, polyalanine, polyglycine, sodium
polygultamate, sodium polyaspartate, polylysine, and polyleucine.
Saccharides, polysaccharides, and water-soluble polysaccharides
include, for example, fructose, sucrose, lactose, dextran,
cyclodextrin, mannitol, and sorbitol. A stabilizer includes one
which is used for the proteinaceous physiologically active
substances, such as albumin, gelatin, mannitol, and trehalose.
Suitable preservatives include, but are not limited to,
p-hydroxybenzoates, sorbic acid, and salicylic acid. Suitable
buffers include, but are not limited to, citrate buffer, acetate
buffer, and phosphate buffer. Suitable sweeteners include, but are
not limited to, mannitol, glucose, maltose, starch, and lactose.
Suitable flavors include, but are not limited to, aspartic acid,
citric acid, and lactic acid. Suitable binder include, but are not
limited to, methylcellulose, ethylcellulose, and carboxy methyl
cellulose. Suitable suspending agents include, but are not limited
to, Tween 20 and Tween 80. Suitable disintegrators include, but are
not limited to, glycerol and starch.
[0190] Dosage unit forms for buccal administration may be in the
form of a hard candy (e.g. lollipops and mints) or a film, e.g., a
slow dissolving film or a fast dissolving film (such as that
described in U.S. Pat. No. 6,596,298, which is hereby incorporated
by reference). Such films can be prepared by including a film
forming agent in the dosage unit form. Suitable film forming agents
include, but are not limited to, those described in U.S. Pat. No.
6,596,298 (e.g., pullulan, hydroxypropylmethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl
pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium
alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar
gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate
copolymer, carboxyvinyl polymer, amylose, high amylose starch,
hydroxypropylated high amylose starch, dextrin, pectin, chitin,
chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy
protein isolate, whey protein isolate, casein and mixtures thereof.
According to one embodiment, the concentration of film forming
agent in the dosage unit form ranges from about 0.01 to about 99 wt
%, from about 30 to about 80 wt %, from about 45 to about 70 wt %,
or from about 60 to about 65 wt % (based upon 100% total weight of
the film). Administration compositions can also take the form of a
pouch that can be placed next to the cheek, or between the lower
teeth and lip, similar to smoke-less tobacco products.
[0191] The compounds and compositions of the subject invention are
useful for administering biologically or chemically active agents
to any animals, including but not limited to birds such as
chickens; fish, reptiles, mammals, such as rodents, cows, pigs,
dogs, cats, primates, and particularly humans, and insects.
EXAMPLES
[0192] The following examples illustrate the invention without
limitation. All parts are given by weight unless otherwise
indicated.
Example 1
Buccal Delivery of PYY.sub.[3-36] in Beagle Dogs
[0193] About 1 mg of PYY solid powder was gradually added and
blended with about 100 mg Delivery Agent (SNAD). Upper punch, lower
punch and die of Carver 4350 manual pellet press with a Caplet
shape model sold by Natoli Engineering Company, Inc. were treated
with magnesium stearate (0.1%). About 101 mg of mixed powder was
fed into the die and a mini bead shape tablet was made at about
1000 PSI. The resulting solid dosage form was about 5 mm diameter
and about 1 mm in height.
[0194] Two male and two female Beagle dogs weighing between 10.2
and 12.7 kg were fasted overnight before the experiments. The
animals were moderately sedated using 0.4-0.8 mg/kg midazolam and
0.03-0.04 mg/kg medetomidine. Once sedated, an intravenous catheter
was placed on the cephalic vein for blood sampling.
[0195] The solid dosage form was placed under the dog's tongue. To
facilitate the dissolution of the tablet, about 0.75 ml of saline
solution was infused slowly under the tongue on the right side and
another 0.75 ml on the left side. One hour post-administration, any
remaining formulation was removed by syringe aspiration and the
sublingual area was rinsed once with saline solution, removing it
afterwards by syringe aspiration.
[0196] Blood samples (about 0.5 ml) were collected serially from
the cephalic vein, typically at time=0 (predose), 15, 30, 45, 60,
90, 120, 150, and 180 minutes post dose. The samples were placed in
serum separating tubes and left at room temperature for 30-45
minutes to allow clotting. The samples were then centrifuged at
about 2-8.degree. C. for 10 minutes at 2500 rpm. The resulting
serum was transferred into a tube and placed on dry ice and then
stored frozen at -70.+-.10.degree. C. until assayed. Serum PYY
concentrations were quantified using a PYY[3-36] radioimmunoassay
(Catalog #RK-059-02 from Phoenix Pharmaceuticals, Inc., Belmont,
Calif.). Results from the animals in each group were averaged for
each time point. The results (.+-.standard error) are shown in FIG.
1.
[0197] Any information regarding specific mechanism(s) is provided
for only background purposes. The invention should not be construed
to be limited, in any way, by any description of the mechanism(s)
by which the delivery agents or active agents (e.g., PYY, PYY
agonists) may function.
[0198] The above-mentioned patents, applications, test methods, and
publications are hereby incorporated by reference in their
entirety.
[0199] Many variations of the present invention will suggest
themselves to those skilled in the art in light of the above
detailed description. All such obvious variations are within the
fully intended scope of the appended claims.
* * * * *