U.S. patent application number 17/335610 was filed with the patent office on 2022-05-12 for peptide yy pharmaceutical formulations, compositions, and methods.
The applicant listed for this patent is Gila Therapeutics, Inc.. Invention is credited to Andres ACOSTA, Beth Anne-Szkudlarek BROWN, Thomas VASICEK.
Application Number | 20220143146 17/335610 |
Document ID | / |
Family ID | 1000005622706 |
Filed Date | 2022-05-12 |
United States Patent
Application |
20220143146 |
Kind Code |
A1 |
ACOSTA; Andres ; et
al. |
May 12, 2022 |
PEPTIDE YY PHARMACEUTICAL FORMULATIONS, COMPOSITIONS, AND
METHODS
Abstract
Pharmaceutical compositions comprising PYY (e.g., PYY(3-36) and
analogs and variants thereof), satiety peptides, satiety hormones,
metabolic hormones, and methods of treating metabolic diseases with
such compositions are provided. Aspects include methods of
increasing a feeling of fullness in patients treated with
pharmaceutical compositions comprising PYY, PYY(3-36), satiety
peptides, satiety hormones, metabolic hormones, and analogs,
receptor antagonists and variants thereof.
Inventors: |
ACOSTA; Andres; (Rochester,
MN) ; VASICEK; Thomas; (Minneapolis, MN) ;
BROWN; Beth Anne-Szkudlarek; (Plymouth, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gila Therapeutics, Inc. |
Minneapolis |
MN |
US |
|
|
Family ID: |
1000005622706 |
Appl. No.: |
17/335610 |
Filed: |
June 1, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16255105 |
Jan 23, 2019 |
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17335610 |
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62669191 |
May 9, 2018 |
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62620580 |
Jan 23, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/183 20130101;
A61K 38/22 20130101; A61K 47/12 20130101; A61K 9/2027 20130101;
A61K 9/4858 20130101; A61K 9/2018 20130101; A61P 3/04 20180101;
A61K 9/2013 20130101; A61K 9/4866 20130101; A61K 9/2054 20130101;
A61K 9/006 20130101; A61K 9/0063 20130101; A61K 47/26 20130101;
A61K 9/0075 20130101; A61K 47/02 20130101; A61K 9/0056 20130101;
A61K 47/38 20130101; A61K 47/32 20130101; A61K 9/1623 20130101;
A61K 9/205 20130101; A61K 9/19 20130101; A61K 9/0058 20130101; A61K
47/46 20130101; A61K 47/10 20130101 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61P 3/04 20060101 A61P003/04; A61K 9/00 20060101
A61K009/00; A61K 47/38 20060101 A61K047/38; A61K 9/48 20060101
A61K009/48; A61K 9/20 20060101 A61K009/20; A61K 47/02 20060101
A61K047/02; A61K 9/16 20060101 A61K009/16; A61K 47/26 20060101
A61K047/26; A61K 47/10 20060101 A61K047/10; A61K 47/12 20060101
A61K047/12; A61K 47/46 20060101 A61K047/46; A61K 9/68 20060101
A61K009/68; A61K 47/32 20060101 A61K047/32; A61K 9/19 20060101
A61K009/19; A61K 47/18 20060101 A61K047/18 |
Claims
1. A pharmaceutical composition comprising an agent selected from
the group consisting of leptin, amylin, calcitonin, gastric
inhibitory peptide (GIP), fibroblast growth factor (FGF21), and
insulin, wherein the composition provides satiation to a subject
without substantially changing the concentration of the agent in
the plasma of the subject, and wherein the composition is
formulated as an oral dissolving tablet.
2. The pharmaceutical composition of claim 1, further comprising
from about 2.5 ng to about 2.5 mg Peptide YY (PYY).
3-9. (canceled)
10. A pharmaceutical composition comprising an agent selected from
oxyntomodulin (OXM) and cholecystokinin (CCK) in a dose of from
about 2.5 ng to about 2.5 mg, wherein the composition provides
satiation to a subject without substantially changing the
concentration of the agent in the plasma of the subject, and
wherein the composition is formulated as an oral dissolving
tablet.
11. The pharmaceutical composition of claim 10, further comprising
from about 2.5 ng to about 2.5 mg PYY.
12-14. (canceled)
15. A pharmaceutical composition comprising an agent selected from
the group consisting of acetyl-CoA carboxylase inhibitor, a
diacylglycerol O-acyltransferase 1 inhibitor, monoacylglycerol
O-acyltransferase inhibitors, a phosphodiesterase-10 inhibitor, an
AMP-activated protein kinase activator, a sulfonylurea, a
meglitinide, an .alpha.-amylase inhibitor, an .alpha.-glucoside
hydrolase inhibitor, an .alpha.-glucosidase inhibitor, a peroxisome
proliferator-activated receptor (PPAR) gamma agonist, a PPAR
.alpha./.gamma. agonist, a biguanide, a protein tyrosine
phosphatase-1B inhibitor, sirtuin-1 activator, a dipeptidyl
peptidase IV inhibitor, an insulin secreatagogue, a fatty acid
oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal
kinase inhibitor, glucokinase activators, an insulin mimetic, a
glycogen phosphorylase inhibitor, a vasoactive intestinal peptide
receptor 2 receptor agonist, a sodium glucose co-transporter 2
inhibitor, a glucagon receptor modulator, a G protein-coupled
receptor 19 modulator, a free fatty acid receptor 1 agonist, a free
fatty acid receptor 4 modulators, a high affinity nicotinic acid
receptor activator, a sodium-D-glucose cotransporter inhibitor, an
inhibitor or modulator of a carnitine palmitoyl transferase enzyme,
a fructose 1,6-diphosphatase inhibitor, an aldose reductase
inhibitor, a mineralocorticoid receptor inhibitor, a target of
rapamycin kinase multiprotein complex inhibitor, a C--C chemokine
receptor type 2 and/or a C--C chemokine receptor type 5 inhibitor,
a protein kinase C inhibitor, a fatty acid synthetase inhibitor, a
serine palmitoyl transferase inhibitor, a G protein-coupled
receptor 81 modulator, a G protein-coupled receptor 39 modulator, a
G protein-coupled receptor 43 modulator, a G protein-coupled
receptor 41 modulator, a G protein-coupled receptor 105 modulator,
voltage-gated potassium channel, retinal binding protein 4,
glucocorticoid receptor, a somatostatin receptor, an inhibitor or
modulator of pyruvate dehydrogenase kinase isoform 2 or pyruvate
dehydrogenase kinase isoform 4, an inhibitor of mitogen-activated
protein kinase kinase kinase kinase 4, an interleukin 1 modulator,
a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, a
squalene synthetase inhibitor, a fibrate, a bile acid sequestrant,
an acyl-CoA cholesterol acyltransferase, a microsomal triglyceride
transfer protein, a lipooxygenase inhibitor, a cholesterol
absorption inhibitor, a proprotein convertase subtilisin/kexin type
9 modulator, a cholesteryl ester transfer protein inhibitor, a
modulator of retinoid x receptor .alpha., enterostatin or an
enterostatin analog, a ghrelin modulator, a pancreatic polypeptide,
neuropeptide Y, human growth hormone, prolactin, oxytocin, bovine
growth hormone, porcine growth hormone, ghrelin, and glucagon,
wherein the composition provides satiation to a subject without
substantially changing the concentration of the agent in the plasma
of the subject, and wherein the composition is formulated as an
oral dissolving tablet.
16. The pharmaceutical composition of claim 15, further comprising
from about 2.5 ng to about 2.5 mg PYY.
17. (canceled)
18. A method of treating a metabolic disorder in a subject
comprising administering the pharmaceutical composition of claim 1
to the tongue of the subject, wherein the composition provides
satiation to a subject without substantially changing the
concentration of the agent in the plasma of the subject.
19. The method of claim 18, wherein the pharmaceutical composition
further comprises from about 2.5 ng to about 2.5 mg PYY.
20-22. (canceled)
23. A method of treating a metabolic disorder in a subject
comprising administering the pharmaceutical composition of claim 10
to the tongue of the subject in a dose of from about 2.5 ng to
about 2.5 mg, wherein the composition provides satiation to a
subject without substantially changing the concentration of the
agent in the plasma of the subject.
24. The method of claim 23, wherein the pharmaceutical composition
further comprises from about 2.5 ng to about 2.5 mg PYY.
25-27. (canceled)
28. A method of treating a metabolic disorder in a subject
comprising administering the pharmaceutical composition of claim 15
to the tongue of the subject wherein the composition provides
satiation to a subject without substantially changing the
concentration of the agent in the plasma of the subject.
29. The method of claim 28, wherein the pharmaceutical composition
further comprises from about 2.5 ng to about 2.5 mg PYY.
30-32. (canceled)
Description
[0001] All references cited herein, including but not limited to
patents and patent applications, are incorporated by reference in
their entirety.
BACKGROUND
[0002] The prevalence of obesity continues to increase worldwide
[1]. In the United States, 69% of adults are overweight or obese
[2]. However, there is still a lack of effective, long-term,
noninvasive treatments for obesity. The current "one treatment fits
all" approach to obesity is associated with highly variable
efficacy and outcomes [3].
[0003] PYY(3-36) is a Y receptor (e.g., Y2 receptor) agonist
released from intestinal cells in response to feeding. Peptide YY
(PYY) (3-36) is a satiation gut hormone released postprandially,
mainly by the gut. PYY(3-36) secretion is related to caloric
intake, and it induces satiation by acting on Y2 receptors in the
arcuate nucleus of the hypothalamus. Recently, murine and human
PYY(3-36) was found to be present in saliva, and its concentration
in saliva is correlated to its concentration in plasma. PYY(3-36)
and Y2 receptors are expressed in the taste cells in the
circumvallate papilla of the tongue [4]. In mice, acute
augmentation therapy with salivary PYY(3-36) induces higher
satiation shown by feeding behavioral studies, and by c-Fos
activation in the arcuate nucleus of the hypothalamus. Acute
increase of salivary PYY(3-36) resulted in a decrease in one-hour
food intake in a dose dependent manner. The chronic over-expression
of salivary PYY(3-36) using a viral vector-mediated gene delivered
(rAAV-PYY vs rAAV-GFP control) into submandibular salivary glands
produced a two-fold chronic increase of PYY(3-36) in saliva for 22
weeks [4]. The results of this treatment showed a decrease in
weekly food intake, and a 23% body weight loss 8 weeks after vector
delivery compared to a control. PYY(3-36) induces satiation through
saliva and taste cell receptors [5,6].
[0004] Incretins, such as glucagon-like peptide 1 (GLP-1), enhance
glycemic control, impede gastric emptying, and increase satiation
in healthy and in diabetic patients [7-9]. GLP-1 and GLP-1 agonists
reduce fasting and postprandial glucose levels via increased
insulin secretion from the pancreas, and reduced gluconeogenesis in
the liver.
[0005] Exenatide (Exendin-4) is a 39-amino acid peptide produced in
the salivary gland of the Gila monster lizard. Its amino acid
sequence shares 53% identity with GLP-1, but its half-life is
prolonged due to its resistance to rapid breakdown by dipeptidyl
peptidase 4 (DPP-IV), the normal mechanism for GLP-1 inactivation.
Exenatide, in both daily and weekly formulations, has been approved
by the FDA for treatment of patients with type 2 diabetes mellitus,
where treatment with metformin or sulfonylureas inadequately
controls the patient's condition. GLP-1 receptor agonists also
retard gastric emptying and decrease food intake by 19% [10-12].
The effects of exenatide on gastric emptying are temporally
associated with reduced postprandial glycemia in patients with type
2 diabetes mellitus [13].
[0006] Previously, PYY and PYY analogs were administered to
patients in a manner resulting in a substantial increase in PYY
levels in the plasma of the subject. PYY and PYY analogs have also
been used to induce satiation in a subject without substantially
changing the concentration of PYY in the plasma of the subject.
See, e.g., U.S. Pat. No. 9,492,505. Higher doses of PYY may result
in undesirable side effects such as nausea. However, suitable
low-dose PYY pharmaceutical formulations for inducing a feeling of
fullness in a subject have not been described.
SUMMARY
[0007] It has been shown that local oral delivery of PYY(3-36)
reduces food intake and increases satiety. However, it is desirable
to improve the activity of PYY(3-36), PYY analogs, and satiety
peptides by providing a suitable low-dose formulation to induce a
long lasting feeling of fullness in a subject. In addition, such
formulations can be used for treatment of metabolic disorders.
[0008] Aspects described herein provide pharmaceutical compositions
comprising PYY or PYY analogs (e.g., PYY(3-36)), variants, and
satiety peptides (e.g., GLP-1, oxyntomodulin, and cholecystokinin)
wherein the dose of PYY or PYY analogs, variants, and satiety
peptides in the pharmaceutical composition is at least about 2.5
ng. In another aspect, PYY is PYY(3-36). In yet another aspect, the
dose of PYY in the pharmaceutical composition is from about 2.5 ng
to about 2.5 mg. In another aspect, the dose of PYY in the
pharmaceutical formulation is from about 2.5 .mu.g to about 250
.mu.g. The term "dose" refers to an amount in the range of 90 to
110% of the desired amount of an active pharmaceutical ingredient
in a dosage form or the claimed amount on a label for a Federal
Drug Administration (FDA) approved drug product.
[0009] In another aspect, the dose per volume of PYY(3-36) can
range, for example, from about 2.5 ng to about 250 .mu.g in a
volume from about 25 .mu.l to about 100 .mu.l or up to about 5 mls.
In another aspect, the dose/volume is about 2.5 .mu.g/ml. In
another aspect, the dose/volume is about 500 .mu.g/500 .mu.L. In
another aspect, the dose/volume is about 250 .mu.g/ml.
[0010] In these aspects, the pharmaceutical compositions can
further comprise pharmaceutically acceptable excipients (e.g.,
propylene glycol, potassium sorbate, l-arginine, edetate disodium,
monosodium phosphate, and polysorbate 20). Optionally, the
pharmaceutical formulations further comprise water or any other
suitable diluent or pharmaceutically acceptable excipient. In one
aspect, the pharmaceutical composition comprises excipients that
further stabilize PYY(3-36) at a low dose per volume (e.g., less
than 2.5 ng/ml). In other aspects, the excipients increase
residence time of the pharmaceutical compositions on the tongue,
for example, promoting binding of PYY(3-36) to its receptor (e.g.,
Y2 receptor). In yet another aspect, excipients can be used to
increase retention time of PYY(3-36) in the saliva, to the extent
such an increase is desirable.
[0011] In another aspect, the pH of the pharmaceutical compositions
is maintained at a pH which promotes the activity and stability of
PYY(3-36). In one aspect, the pH of the pharmaceutical composition
is between about pH 5 to about 8. In another aspect, the pH of the
pharmaceutical composition is between about pH 6 to about 7. In yet
another aspect, the pH is about 5.
[0012] In one aspect, the described pharmaceutical formulations can
be used to treat metabolic disorders (e.g., obesity, elevated blood
sugar, diabetes, fatty liver disease, PCOS, and multiple sclerosis)
by administering PYY and PYY analog formulations to a subject, and
reducing symptoms associated with the metabolic disorders compared
to a subject that has not received PYY or PYY analog
formulations.
[0013] Yet another aspect provides methods of increasing a feeling
of fullness in a subject by administering a PYY or a PYY analog
formulation to the subject, for example, before a meal. In this
aspect, the feeling of fullness can last at least about 30, 60, 90,
or 120 minutes or longer after the PYY or PYY analog formulation is
administered to subject and after the subject has eaten a meal. In
another aspect, the pharmaceutical composition is administered to
the subject, and the subject subsequently consumes a meal.
BRIEF DESCRIPTION OF DRAWINGS
[0014] FIG. 1 shows the results of an exemplary study where
PYY(3-36) was administered intraorally to subjects at the indicated
dose (GT-001 Dose on the x-axis), and a feeling of fullness (mean
value on y-axis) was assessed 30 minutes and 120 minutes after the
subjects ate lunch;
[0015] FIG. 2 shows the results of an exemplary study where the
feeling of fullness (VAS Fullness (mm)) was plotted against the
time post-treatment with PYY(3-36) (30 min, 60 min, 90 min, and 120
min) with a PYY(3-36) formulation, and after the subjects ate lunch
at four doses (placebo, 25 ng, 25 .mu.g, and 250 .mu.g); and
[0016] FIG. 3 shows the normalized concentration in pg/ml of PYY in
the plasma of subjects receiving placebo, 0.25 mg/ml PYY(3-36), and
2.5 mg/ml PYY(3-36) formulations (each followed by lunch) measured
in a time range of up to 4 hours after administration.
DETAILED DESCRIPTION
[0017] Before describing an exemplary aspect described herein, it
is to be understood that the invention is not limited to the
details of construction or process steps set forth in the following
description. The aspects described herein are capable of being
practiced or being carried out in various ways.
[0018] Satiation occurs during a meal. It's that point at which a
subject feels that she has had enough to eat, and does not desire
any more food. Satiety, on the other hand, describes a subject's
experience after a mealhow long before the subject starts to feel
hungry again. A "feeling of fullness" refers to an indicator of
satiety as reported by a person following the eating of food or a
meal. The degree and duration of a feeling of fullness (satiation
and satiety) are predictor of whether a person will continue to eat
or resume eating and therefore increase caloric intake over time.
Thus, increasing the degree and duration of a feeling of fullness
reduces overall caloric intake and a reduction in weight and
obesity.
[0019] A Visual Analogue Scale (VAS) is an instrument, tool, or
methodology used to measure a characteristic that can vary in value
or degree, and is otherwise not easily subject to direct
measurement. For example, a VAS is often used to determine the
degree of pain suffered by a patient (e.g., a scale of 1 to 10).
Likewise, a VAS can be used reliably to measure the degree of
fullness reported by a subject following the eating of food or a
meal. See, e.g., Blundell et al., "Appetite Control: Methodological
Aspects of The Valuation of Foods," Obes Rev. 2010 March; 11(3):
251-270; Flint et al., "Reproducibility, power and validity of
visual analogue scales in assessment of appetite sensations in
single test meal studies," International Journal of Obesity (2000)
24, 38-48 (2000).
[0020] Metabolic disorders, diseases, or metabolic syndrome refers
to diseases or conditions that increase risk for diseases or
disorders associated with, related to, or caused by abnormal
metabolism (e.g., diabetes, heart disease, stroke, obesity,
elevated blood sugar, fatty liver disease, PCOS (polycystic ovary
syndrome), and multiple sclerosis). The lack of effective long
term, non-invasive procedures for metabolic disorders has spurred
the search for small molecules capable of treating these conditions
with minimal side effects. While several small molecule
therapeutics are currently on the market, their efficacy is
relatively low, and safety profiles are less than ideal. On the
other hand, natural human hormones responsible for regulation of
hunger, satiety and energy metabolism in normal physiology, and
their analogs, as described herein, can be used to treat such
diseases.
[0021] GLP-1 receptor agonists, and PYY(3-36) and analogs have been
used with limited success in treating metabolic disorders.
Therapeutic outcomes with GLP-1 receptor agonists for diabetes
mellitus (DM) and obesity are highly variable, and result in
significant side effects. While PYY(3-36) is a strong inducer of
satiety, systemically administered PYY and analogs tend to be
associated with severe side effects, such as nausea and
vomiting.
[0022] Aspects described herein provide compositions comprising PYY
and PYY analogs such as PYY(3-36). In certain aspects, these
compositions can be used to treat metabolic diseases (e.g.,
obesity, diabetes, elevated blood sugar, etc.). These compositions
can be used to reduce, ameliorate, or treat conditions in patients
more effectively than simple aqueous solutions or simple dry
compositions.
[0023] In one aspect, the term "PYY(3-36)" or "native PYY-3-36"
refers to amino acids 3-36 of the human PYY molecules, having the
following amino acid sequence (from amino to carboxy terminus):
TABLE-US-00001 {NH2}-ILE-LYS-PRO-GLU-ALA-PRO-GLY-GLU-ASP-ALA-SER-
PRO-GLU-GLU-LEU-ASN-ARG-TYR-TYR-ALA-SER-LEU-ARG-
HIS-TYR-LEU-ASN-LEU-VAL-THR-ARG-GLN-ARG-TYR- {COOH}.
[0024] Native PYY(3-36) is post-translationally processed from a
precursor peptide encoded by the following mRNA nucleic acid
sequence (positions 632-733 (bolded below)) encode the mature
peptide):
TABLE-US-00002 1 gcccctggag gaactgaacc cactatcggt catggggccg
agactaaatg tggcgggttg 61 tctttaatct gctgccaaga ggaaactcat
tcaggcaagt tcagcccttt atgaggaatt 121 cccctgtggt cacattccaa
ttcctggacc tgctgccacc ctcagaactg catgctcctt 181 cttcagactt
tctaagaatg actcaggtca ttggtggagt gaagtcaaga tttccaactc 241
agtcacctga agagatggag ataccattca tggagctgga ggtccctgga gatttgggaa
301 ttcagataac aagctaagat aaggagtttg cctacctctg tcctagagcg
aagcctgagc 361 cttgggcgcg cagcacacca caagtatctg ttactgtgtt
ttgcagaagc ttcaggcggg 421 gatataagcc ccacaaggaa agcgctgagc
agaggaggcc tcagcttgac ctgcggcagt 481 gcagcccttg ggacttccct
cgccttccac ctcctgctcg tctgcttcac aagctatcgc 541 tatggtgttc
gtgcgcaggc cgtggcccgc cttgaccaca gtgcttctgg ccctgctcgt 601
ctgcctaggg gcgctggtcg acgcctaccc catcaaaccc gaggctcccg gcgaagacgc
661 ctcgccggag gagctgaacc gctactacgc ctccctgcgc cactacctca
acctggtcac 721 ccggcagcgg tatgggaaaa gagacggccc ggacacgctt
ctttccaaaa cgttcttccc 781 cgacggcgag gaccgccccg tcaggtcgcg
gtcggagggc ccagacctgt ggtgaggacc 841 cctgaggcct cctgggagat
ctgccaacca cgcccacgtc atttgcatac gcactcccga 901 ccccagaaac
ccggattctg cctcccgacg gcggcgtctg ggcagggttc gggtgcggcc 961
ctccgcccgc gtctcggtgc ccccgccccc tgggctggag ggctgtgtgt ggtccttccc
1021 tggtcccaaa ataaagagca aattccacag aaacggaaaa aaaaaaaaa
[0025] In another aspect, the term "PYY(3-36)" further comprises
analogs or variants of native PYY(3-36) that retain at least about
20, 30, 40, 50, 60, 70, 80, 90 or 100% of the biological activity
of native PYY(3-36). In this aspect, term "variants" refers to
modifications to or substitutions of one or more amino acids of
native PYY(3-36). Substitution of an amino acid refers to
replacement of one amino acid with another amino acid. In one
aspect, an amino acid may be replaced with an amino with a similar
side group (e.g., acidic, basic, neutral). The term "biological
activity" refers to the activation of Y receptors by one or more
small molecules described herein, producing an effect, either
locally or systemically, on food intake, gastrointestinal function
or central nervous system activity.
[0026] Analogs or variants of PYY(3-36) include, for example, the
analogs or variants of PYY. See, e.g., Michel et al., Dipeptidyl
peptidase IV inhibitors in diabetes; more than inhibition of
glucagon-like peptide-1 metabolism? Naunyn-Schmiedeberg's Arch
Pharmacol (2008) 377:205-207; Niida et al., Antiobesity and emetic
effects of a short-length peptide YY analog and its PEGylated and
alkylated derivatives, Bioorganic & Medicinal Chemistry (2017)
(S0968-0896 (Epub ahead of print). In one aspect, these analogs and
variants can be used in the pharmaceutical compositions described
herein.
[0027] Aspects described herein provide pharmaceutical compositions
comprising PYY, wherein the dose of PYY provided to a subject is at
least about 2.5 ng when the PYY is administered to the subject. In
another aspect, PYY is PYY(3-36). In yet another aspect, the dose
of PYY, PYY(3-36), or other PYY analogs is about 25 ng, 250 ng, 2.5
.mu.g, 25 .mu.g, 250 .mu.g, or 2.5 mg. In further aspects, the dose
of PYY, PYY(3-36), or other PYY analogs can range from about 25 ng
to about 2.5 mg, from about 250 ng to about 250 .mu.g, or from
about 2.5 .mu.g to about 25 .mu.g.
[0028] Further aspects provide a pharmaceutical composition,
comprising a satiety peptide in a dose of about 2.5 ng to about 2.5
mg, and a pharmaceutically acceptable excipient. In another aspect,
the pharmaceutical composition of claim 23, wherein the satiety
peptide is selected from the group consisting of GLP-1,
oxyntomodulin, and cholecystokinin.
[0029] In another aspect, the dose per volume of PYY(3-36) can
range, for example, from about 2.5 ng to about 250 .mu.g in a
volume from about 25 .mu.l to about 5 mls of solvent (e.g., water,
buffer, etc.). In another aspect, the dose/volume is about 2.5
.mu.g/ml. In another aspect, the dose/volume is about 500 .mu.g/500
.mu.l. The volume of a pharmaceutical formulation selected for
delivering a dose of PYY(3-36) can be selected, for example, to
optimize the residency time of PYY(3-36) in the oral cavity and,
more specifically, the tongue in order to increase the interaction
between PYY(3-36) and its receptor on the tongue (e.g., Y2
receptor).
[0030] Further aspects comprise these pharmaceutical compositions
comprising nucleotides encoding or peptides having substantial
identity to PYY, PYY(3-36), or other PYY analogs in addition to one
or more of the following, or with one or more of the following in
place of PYY, PYY(3-36), or other PYY analogs: GLP-1,
oxyntomodulin, and cholecystokinin acetyl-CoA carboxylase-(ACC)
inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor,
monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase
(PDE)-10 inhibitor, an AMPK activator, a sulfonylurea, a
meglitinide, an .alpha.-amylase inhibitor, an .alpha.-glucoside
hydrolase inhibitor, an .alpha.-glucosidase inhibitor, a
PPAR.gamma. agonist, a PPAR .alpha./.gamma. agonist, a biguanide, a
glucagon-like peptide 1 (GLP-1) modulator, GLP-1 receptor agonists,
liraglutide, albiglutide, exenatide, albiglutide, lixisenatide,
dulaglutide, semaglutide, a protein tyrosine phosphatase-1B
(PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl peptidease IV
(DPP-IV) inhibitor, an insulin secreatagogue, a fatty acid
oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal
kinase (JNK) inhibitor, glucokinase activators (GKa), insulin, an
insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2
receptor agonist, SGLT2 inhibitors, a glucagon receptor modulator,
GPR119 modulators, FGF21 derivatives or analogs, TGR5 receptor
modulators, GPBAR1 receptor modulators, GPR40 agonists, GPR120
modulators, high affinity nicotinic acid receptor (HM74A)
activators, SGLT1 inhibitors, inhibitors or modulators of carnitine
palmitoyl transferase enzymes, inhibitors of fructose
1,6-diphosphatase, inhibitors of aldose reductase,
mineralocorticoid receptor inhibitors, inhibitors of TORC2,
inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g.
PKC.alpha., PKC.beta., PKC.gamma.), inhibitors of fatty acid
synthetase, inhibitors of serine palmitoyl transferase, modulators
of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding
protein 4, glucocorticoid receptor, somato stain receptors,
inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4,
modulators of IL1 family including IL1beta, HMG-CoA reductase
inhibitors, squalene synthetase inhibitors, fibrates, bile acid
sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase
inhibitors, cholesterol absorption inhibitors, PCSK9 modulators,
cholesteryl ester transfer protein inhibitors and modulators of
RXR.alpha., GIP receptor agonists, enterostating and enterostatin
analogs, amylin and amylin receptor agonists, ghrelin modulators
(e.g., inhibitors) and leptin and leptin receptor agonists,
pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY),
human growth hormone, prolactin, oxytocin, bovine growth hormone,
porcine growth hormone, ghrelin, ghrelin receptor antagonists, and
glucagon and analogs and variants thereof.
[0031] In yet another aspect, pharmaceutical compositions
comprising one or more active pharmaceutical ingredients selected
from the group consisting of PYY, PYY(3-36), GLP-1, oxyntomodulin,
and cholecystokinin, acetyl-CoA carboxylase-(ACC) inhibitor, a
diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor,
monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase
(PDE)-10 inhibitor, an AMPK activator, a sulfonylurea, a
meglitinide, an .alpha.-amylase inhibitor, an .alpha.-glucoside
hydrolase inhibitor, an .alpha.-glucosidase inhibitor, a
PPAR.gamma. agonist, a PPAR .alpha./.gamma. agonist, a biguanide, a
glucagon-like peptide 1 (GLP-1) modulator, GLP-1 receptor agonists,
liraglutide, albiglutide, exenatide, albiglutide, lixisenatide,
dulaglutide, semaglutide, a protein tyrosine phosphatase-1B
(PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl peptidase IV
(DPP-IV) inhibitor, an insulin secreatagogue, a fatty acid
oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal
kinase (JNK) inhibitor, glucokinase activators (GKa), insulin, an
insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2
receptor agonist, SGLT2 inhibitors, a glucagon receptor modulator,
GPR119 modulators, FGF21 derivatives or analogs, TGR5 receptor
modulators, GPBAR1 receptor modulators, GPR40 agonists, GPR120
modulators, high affinity nicotinic acid receptor (HM74A)
activators, SGLT1 inhibitors, inhibitors or modulators of carnitine
palmitoyl transferase enzymes, inhibitors of fructose
1,6-diphosphatase, inhibitors of aldose reductase,
mineralocorticoid receptor inhibitors, inhibitors of TORC2,
inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g.
PKC.alpha., PKC.beta., PKC.gamma.), inhibitors of fatty acid
synthetase, inhibitors of serine palmitoyl transferase, modulators
of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding
protein 4, glucocorticoid receptor, somatostain receptors,
inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4,
modulators of IL1 family including IL1beta, HMG-CoA reductase
inhibitors, squalene synthetase inhibitors, fibrates, bile acid
sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase
inhibitors, cholesterol absorption inhibitors, PCSK9 modulators,
cholesteryl ester transfer protein inhibitors and modulators of
RXR.alpha., GIP receptor agonists, enterostating and enterostatin
analogs, amylin and amylin receptor agonists, ghrelin modulators
(e.g., inhibitors) and leptin and leptin receptor agonists,
pancreatic polypeptide (PP), calcitonin, OXM, neuropeptide Y (NPY),
human growth hormone, prolactin, oxytocin, bovine growth hormone,
porcine growth hormone, ghrelin, ghrelin receptor antagonists, and
glucagon and a pharmaceutically acceptable excipient. In this
aspect, these active ingredients can be formulated at therapeutic
doses, and if the second drug is PYY or PYY(3-36), its dose can be
at from about 2.5 ng to about 2.5 mg. The term "therapeutic dose"
refers to a dose at which a pharmaceutically active ingredient can
treat, ameliorate, or reduce symptoms associated with a disease,
disorder, or condition.
[0032] In another aspect, these pharmaceutical compositions further
comprise pharmaceutically acceptable excipients (e.g., propylene
glycol, potassium sorbate, l-arginine, edetate disodium, monosodium
phosphate, and polysorbate 20). In one aspect, propylene glycol is
present in a concentration of about 100 mg/ml, 1-arginine is
present in a concentration of about 25 mg/ml, potassium sorbate is
present in a concentration of about 2 mg/ml, edetate disodium is
present in a concentration of about 1.2 mg/ml, sodium phosphate
monobasic dihydrate is present in a concentration of about 7.8
mg/ml, and polysorbate is present in a concentration of about 5
mg/ml. Further aspects comprise these pharmaceutical compositions
with GLP-1, oxyntomodulin, and cholecystokinin in place of PYY,
PYY(3-36), or other PYY analogs and variants.
[0033] For example, the pharmaceutical compositions described
herein can include co-solvent stabilizers like propylene glycol or
other suitable co-solvent stabilizers (e.g., lower molecular weight
polyethylene glycols (PEG) such as PEG 200 and 400, glycerin, and
ethanol (alcohol)).
[0034] In another aspect, the pharmaceutical compositions described
herein can include amino acid stabilizers like L-Arginine or other
suitable amino acid stabilizers (e.g., alanine, arginine, aspartic
acid, glycine, lysine, proline, and methionine).
[0035] In yet another aspect, the pharmaceutical compositions
described herein can include preservatives like potassium sorbate,
or other suitable preservatives (e.g., ascorbic acid, benzyl
alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol,
glutathione, methionine, methylparaben, propylparaben, sodium
sulfite, parahydroxybenzoate esters (methylhydroxybenzoate and
propylhydroxybenzoate), boric acid and borate salts, sorbic acid
and other sorbate salts besides potassium, and phenolics)).
[0036] In another aspect, the pharmaceutical compositions described
herein can include antioxidants such as edetate disodium or another
suitable antioxidant (e.g., sodium formaldehyde sulphoxylate,
butylated hydroxyanisole, and butylated hydroxytoluene). In another
example, the pharmaceutical compositions described herein can
include buffers like phosphate or other suitable buffers (e.g.,
acetate, carbonate, citrate, citrate-phosphate, glycine, HEPES,
histidine, maleate, phosphate, succinate, tartrate, and
triethanolamine (Tris)). In another example, the pharmaceutical
compositions described herein can include surfactants like
polysorbate 20 or other suitable surfactants (e.g., Poloxamer
188/407, polysorbate 40 or 80, or sodium lauryl sulfate).
[0037] In yet another aspect, the excipients include flavorings to
increase compliance with ingesting the pharmaceutical formulation.
For example, the flavorings can be used to mask bitter or other
undesirable flavor properties, or to make the pharmaceutical
formulation compatible with the flavor of food that may be ingested
before or after the pharmaceutical formulations. Compatible
flavorings include, for example, apple, banana, bubblegum, cherry,
chocolate, grape, lemon, mango, orange, raspberry, strawberry,
vanilla, watermelon, mint or a combination of the above flavors. In
another aspect, these flavorings are dye-free, sugar-free,
hypoallergenic, gluten-free, and casein-free.
[0038] In one aspect, the pharmaceuticals compositions described
herein are adapted for delivery to the oral cavity (e.g.,
intraoral, oromucosal, transmucosal, topical lingual, gargles,
mouthwashes, gingival solutions, oromucosal solutions and
oromucosal suspensions, semi-solid oromucosal preparations
(including for example gingival gel, gingival paste, oromucosal
gel, oromucosal paste)), oromucosal drops, oromucosal sprays and
sublingual sprays (including oropharyngeal sprays), dry powder
sprays, lozenges and pastilles, compressed lozenges, sublingual
tablets and buccal tablets, oromucosal capsules, mucoadhesive
preparations)). See, e.g., Oromucosal Preparations, (Ph Eur
monograph 1807). In another aspect, the PYY in the pharmaceutical
composition is adapted for binding to the Y2 receptor.
[0039] The term "adapted for delivery" refers to a pharmaceutical
formulation or ingredient that has properties or is configured to
be preferentially delivered or bound to a desired area of the body
(e.g., mouth, tongue) or a target (e.g., a receptor). The term
"adapted for delivery to the oral cavity" refers to a
pharmaceutical formulation that can preferentially deliver
PYY(3-36) to the oral cavity or, more specifically, the tongue or
one or more active substances intended for administration to the
oral cavity and/or the throat to obtain a local or systemic effect.
See, e.g., Oromucosal Preparations, (Ph Eur monograph 1807). The
term "adapted for binding to a receptor" or "adapted for binding to
the Y2 receptor," refers to a satiety peptide, analog, or other
active ingredient that has a binding affinity to the Y2 receptor or
residence time on the tongue sufficient to induce satiety (e.g.,
about 30 seconds to about 1 min). In one aspect, "local oral
delivery" can refer to obtaining a local effect without increasing
the levels of an active ingredient in the blood plasma.
[0040] The excipients in such a pharmaceutical formulation are
compatible with the mouth for intraoral delivery, and the active
ingredient in the pharmaceutical formulation can maintain its
activity in the mouth until delivered to its site of activity. In
another aspect, PYY(3-36) is delivered to the tongue, and binds to
a Y receptor (e.g., the Y2 receptor).
[0041] In this aspect, PYY(3-36) can bind to the tongue, and
transmit a signal to the brain via a receptor (e.g., Y2 receptor).
In another aspect, PYY(3-36) can be delivered systemically by any
suitable route of administration (e.g., oral, parenteral,
intravenous, etc.).
[0042] The term "binds" refers to an association between PYY(3-36)
(or other satiety peptides and metabolic hormones as described
herein) or a portion of the PYY(3-36) molecule, and a Y receptor
through a chemical bond (e.g., ionic, covalent, or hydrophobic) or
other chemical or physical attraction between PYY(3-36) or a
portion thereof and a Y receptor where a biological response is
induced by the association between PYY(3-36) and the Y receptor.
See e.g., Doods, Receptor binding profiles of NPY analogues and
fragments in different tissues and cell lines, Peptides. 1995;
16(8):1389-94.
[0043] In another aspect, the pharmaceutical compositions comprise
excipients that increase the time PYY(3-36) is in contact with the
mucosa (e.g., viscosity enhancement, encapsulation, and controlled
release). Without being bound by theory, it is believed that
increasing the contact time of the pharmaceutical formulation with
the mucosa, leads to increased binding of PYY(3-36) to its receptor
on the tongue. Suitable excipients for viscosity enhancement
include rheology modifiers which also may be mucoadhesive such as
methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
alginic acid, polyvinylpyrrolidone, and sodium
carboxymethylcellulose. Suitable excipients for modified release of
the PYY(3-36) in the oral cavity include mucoadhesive permeation
enhancers such as 23-lauryl ether, aprotinin, azone, benzalkonium
chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide,
cyclodextrins, dextran sulfate, and lauric acid. Other suitable
mucoadhesive polymers used for buccal or intraoral delivery include
agarose, chitosan, gelatin, hyaluronic acid, gums (e.g. guar,
hakea, xanthan, gellan, carrageenan, pectin, and sodium alginate),
cellulose derivatives (e.g., CMC, thiolated CMC, sodium CMC, HEC,
HPMC, MC, methylhydroxylethylcellulose), poly (acrylic acid)-based
polymers (e.g., CP, PC, PAA, polyacrylates,
poly(methylvinylether-co-methacrylic acid), poly(2-hydroxyethyl
methacryalate), poly(alkylcyanoacryalate),
poly(isohexylcyanocrylate), poly(isobutylcyanoacrylate), copolymer
of acrylic acid and PEG, poly(N-2-hydroxypropyl methacrylamide),
PHPMAm, polyoxyethylene, PVA, PVP, and other thiolated polymers;
scleroglucan, PVA, steroidal detergents, non-ionic surfactants,
laureth-9, sodium fusidate, included sodium lauryl, sodium laurate
(e.g., pH 8.9), palmitoyl carnitine, lauric acid/propylene glycol
vehicle, Brij 78, sodium deoxycholate, sodium lauryl sulfate,
lecithin and PVP. See, e.g., International Journal of
Pharmaceutics, Volume 53, Issue 3, 1 Aug. 1989, Pages 227-235.
[0044] In another aspect, the pharmaceutical compositions comprise
excipients that increase the residence time of PYY(3-36) in the
saliva (e.g., the amount of time PYY(3-36) remains in the saliva
without significant degradation of the peptide). Without being
bound by theory, it is believed that increasing the residence time
of PYY(3-36) in the saliva increases the opportunity for PYY(3-36)
to bind its receptor on the tongue. The residence time in the
saliva can optionally be adjusted to avoid increasing systemic
exposure to PYY(3-36) through, for example, swallowing.
[0045] The term "pharmaceutically acceptable excipients" includes,
for example:
[0046] (1) Stabilizers (e.g., co-solvents like propylene glycol,
polyethylene glycols (PEG), glycerin, and ethanol (alcohol)) and
amino acids (e.g., alanine, L-Arginine, arginine, aspartic acid,
glycine, lysine, proline, and methionine).
[0047] (2) Preservatives (e.g., potassium sorbate, ascorbic acid,
benzyl alcohol, benzoic acid, citric acid, chlorobutanol, m-cresol,
glutathione, methionine, methylparaben, propylparaben, sodium
sulfite, parahydroxybenzoate esters (methylhydroxybenzoate and
propylhydroxybenzoate), boric acid and borate salts, sorbic acid
and sorbate salts, and phenolics).
[0048] (3) Antioxidants (e.g., edetate disodium, sodium
formaldehyde sulphoxylate, butylated hydroxyanisole, and butylated
hydroxytoluene);
[0049] (4) Buffers (e.g., phosphate, acetate, carbonate, citrate,
citrate-phosphate, glycine, HEPES, histidine, maleate, phosphate,
succinate, tartrate, and triethanolamine (Tris));
[0050] (5) Surfactants (e.g., polysorbate 20, poloxamer 188/407,
polysorbate 20/40/80, and sodium lauryl sulfate);
[0051] (6) Rheology modifiers (e.g., methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, alginic acid,
polyvinylpyrrolidone, and sodium carboxymethylcellulose);
[0052] (7) Mucosal Permeation Enhancers (e.g., 23-lauryl ether,
aprotinin, azone, benzalkonium chloride, cetylpyridinium chloride,
cetyltrimethylammonium bromide, cyclodextrin, dextran sulfate, and
lauric acid);
[0053] (8) Excipients used to stabilize active ingredients in
lyophilized tablets for oral disintegration and dissolution in the
oral cavity including sugars or sugar alcohols such as sucrose,
trehalose, mannitol, dextrose, and polyvinylpyrrolidone (PVP) or
glycine;
[0054] (9) Flavorings like apple, banana, bubblegum, cherry,
chocolate, grape, lemon, mango, orange, orange swirl, raspberry,
strawberry, strawberry swirl, vanilla, walberry swirl, and
watermelon (including dye-free, sugar-free, hypoallergenic,
gluten-free, and casein-free versions); and sweetening agents,
including sucrose, liquid glucose, glycerol, sorbitol, saccharin
sodium and aspartame); and
[0055] In one aspect, delivery of PYY(3-36) compositions to the
tongue minimizes or eliminates any substantial systemic delivery of
PYY(3-36). The term "substantial systemic delivery" refers to blood
levels of administered PYY(3-36) or its analogs or variants that
exceed the limit of detection, are distinguishable from circulating
levels, or cause a significant increase in circulating levels.
[0056] Further aspects provide methods of treating metabolic
disorders or diseases in a subject. In another aspect, the
metabolic disease can be selected from the group consisting of
obesity, elevated blood sugar (e.g., elevated blood sugar levels),
diabetes, fatty liver disease, high blood pressure, PCOS, and
multiple sclerosis. In these aspects, "treatment" or "treat" refers
to administering PYY (e.g., PYY(3-36)) or another PYY analog) to a
patient having the indicated metabolic disease.
[0057] When the metabolic disorder is obesity, food intake by the
subject is reduced by at least about 20% in the subject after
treatment with a dose of the pharmaceutical composition compared to
a subject who did not receive treatment. In another aspect, body
weight of the subject is reduced by at least about 5% after
treatment with a dose of the pharmaceutical composition compared to
a subject who did not receive treatment. In the aspects described
herein, the term "subject" refers to an animal (e.g., human,
non-human) in need of treatment for the indicated disease or
condition.
[0058] When the metabolic disorder is elevated blood sugar (e.g.,
pre-diabetes), the blood sugar or glucose levels of a subject is
reduced by at least about 10% after treatment with a dose of the
pharmaceutical composition compared to a subject who did not
receive treatment. In another aspect, the fasting glucose level is
reduced by at least about 10% after treatment with a dose of the
pharmaceutical composition compared to a subject who did not
receive treatment.
[0059] When the metabolic disease is disorder, the area under the
curve (AUC) in a glucose tolerance test of a subject is reduced by
at least about 15% after treatment with a dose of the
pharmaceutical composition compared to a subject who did not
receive treatment. In another aspect, HbA1c levels in a subject are
reduced by at least about 15% after treatment with a dose of the
pharmaceutical composition compared to a subject who did not
receive treatment.
[0060] When the metabolic disorder is fatty liver disease, the
liver fat concentration in a subject is reduced by about 20% after
treatment with a dose of the pharmaceutical composition compared to
a subject who did not receive treatment. In this aspect, liver fat
concentration can be measured by, for example, liver biopsy,
ultrasound, MRI (magnetic resonance imaging), and elastography.
[0061] When the metabolic disorder is PCOS, PCOS symptoms in a
subject are reduced by at least about 15 to 20% after a dose of the
pharmaceutical composition compared to a subject who did not
receive the dose. In this aspect, the exemplary symptoms include,
but are not limited to, hormonal profile (e.g., thyroid function
tests, serum prolactin levels, and a free androgen index (defined
as total testosterone divided by sex hormone binding globulin
[SHBG].times.100, to give a calculated free testosterone level),
LH2FsH ratio, and testosterone level).
[0062] When the metabolic disorder is multiple sclerosis (MS),
multiple sclerosis symptoms are reduced in a subject by at least
about 20% after treatment with a dose of the pharmaceutical
composition compared to a subject who did not receive treatment. In
this aspect, the symptoms include, but are not limited to, the
Multiple Sclerosis Functional Composite. See, e.g., Cutter et al.,
Development of a multiple sclerosis functional composite as a
clinical trial outcome measure, Brain, 1999 May; 122 (Pt
5):871-82.
[0063] When the metabolic disorder is high blood pressure, systolic
and diastolic blood pressure levels in a subject are reduced by at
least about 20% after treatment with a dose of the pharmaceutical
composition compared to a subject who did not receive treatment. In
this aspect, for example, treatment can be started when systolic
and diastolic blood pressure levels of 140 mm Hg or greater or at
diastolic levels of 90 mm are reached.
[0064] The term "metabolic disorder" refers to a human or animal
condition or disease resulting from abnormal function or control of
the metabolic system (e.g., obesity, diabetes, fatty liver disease,
PCOS, and elevated blood glucose levels). The term "disorder"
generally refers to disruption to regular bodily structure and
function or a pathophysiological response to internal or external
factors.
[0065] Further aspects provide methods of increasing a feeling of
fullness in a subject comprising administering the pharmaceutical
compositions described herein to the subject. In this aspect, the
dose of PYY, PYY(3-36) or a variant or analog can be about 25 ng,
250 ng, 2.5 .mu.g, 25 .mu.g, 250 .mu.g, or 2.5 mg. In further
aspects, the dose of PYY, PYY(3-36) or a variant or analog can
range from about 25 ng to about 2.5 mg, from about 250 ng to about
250 .mu.g, or from about 2.5 .mu.g to about 25 .mu.g. In yet
another aspect, the feeling of fullness in the subject can last at
least 30, 60, 90, or 120 minutes after treatment and after eating a
meal. In another aspect, the pharmaceutical composition is
administered to the subject, and the subject subsequently consumes
a meal.
[0066] In this aspect, the dose per volume of PYY(3-36) can range,
for example, from about 2.5 ng to about 250 .mu.g in a volume from
about 25 .mu.l to about 5 mls. In another aspect, the dose/volume
is 2.5 .mu.g/ml. In another aspect, 500 .mu.g/500 .mu.L. The volume
of a pharmaceutical formulation selected for delivering a dose of
PYY(3-36) can be selected, for example, to optimize the residency
time of PYY(3-36) in the oral cavity and, more specifically, the
tongue in order to increase the interaction between PYY(3-36) and
its receptor on the tongue (e.g., Y2 receptor).
[0067] The term "eating a meal" refers a subject eating food with a
total caloric intake of at least about, for example, 300-2000,
500-1000 calories, or 300-800 calories. The term "feeling of
fullness" refers to a subject self-reporting satiety following
eating a meal as measured using, for example, VAS measurement
wherein the VAS measurement is increased by at least about 10%. In
another aspect, the VAS measure is increased by at least about 20%.
In another aspect, a functional magnetic resonance imaging ("fMRI")
scan before and after treatment can be used to measure a feeling of
fullness (by measuring blood flow changes in specific regions of
the brain, for example the satiety centers of the brain stem, such
as the nuclues tractus solitaris, and the hypothalamus, such as the
lateral hypothalamic area). In yet another aspect, subjects can
verbally report a level of feeling of fullness before and after
treatment. In yet another aspect, subjects can verbally report a
level of feeling of fullness before and after treatment.
[0068] In one aspect, the pharmaceutical compositions comprising
PYY(3-36) can be delivered to a subject in need of treatment
before, after, or during a meal. In this aspect, the pharmaceutical
compositions can be delivered intraorally.
[0069] In one aspect the composition can be incorporated in any
suitable dosage form (e.g., a lozenge, a dissolvable material, a
dissolvable planar sheet, chewing gum, or a solid or semi-solid
candy). In another aspect, the composition can be incorporated in a
liquid formulation (e.g., emulsion, a syrup, an elixir, a
suspension, or a solution). In a further aspect, the composition
can be incorporated in a spray for oral administration, or drops
for oral administration.
[0070] In one aspect, the pharmaceutical composition is as
follows:
TABLE-US-00003 TABLE 1 Exemplary PYY(3-36) Pharmaceutical
Formulation Strength (label claim) Component and Quantity Quality
per unit Standard Function (mg/mL) % PYY.sub.3-36, human Drug
substance 2.5 ng/mL to 2.5 .times. 10.sup.-7 to 0.25% 2.5 mg/mL
Propylene Glycol, Stabilizer 100 10 USP L-Arginine, Free Stabilizer
25 2.5 Base, USP Potassium Sorbate, Preservative 2 0.20 NF Edetate
Disodium, Antioxidant 1.2 0.12 Dihydrate, USP Sodium Phosphate,
Buffer 7.8 0.78 Monobasic, Dihydrate, USP Polysorbate 20, NF
Surfactant 5 0.50 Hydrochloric Acid pH modifier QS to pH (HCl), NF,
USP 7.0 .+-. 0.1 Sodium Hydroxide pH modifier QS to pH (NaOH), USP
7.0 .+-. 0.1 Sterile Water for Solvent QS to QS to Injection, USP 1
mL 100%
[0071] An exemplary clinical trial was performed as a
dose-escalation design trial. Approximately twelve evaluable
subjects (n-12) with BMIs of 30 to 40 kg/m.sup.2 received a single
dose of placebo followed by study drug (PYY(3-36) also known as
GT-001) applied directly to the surface of the lingual mucosa with
a disposable pipette followed by a one-day washout. A total of
seven (7) doses was escalated to a dose of 2.5 mg/ml.
[0072] Without being bound by theory, it is believed that food
intake is regulated by two opposing mechanisms; appetite and
satiation. Both mechanisms are regulated by the brain-gut axis. A
fasting period induces appetite by secretion of ghrelin from the
stomach. Ghrelin acts on specialized neurons in the arcuate nucleus
of the hypothalamus to activate the agouti-related peptide/NPY
(AgRP/NPY) pathway. The AgRP/NPY pathway is responsible for
stimulating appetite centers in the cerebral cortex that prepare
the gastrointestinal tract for food intake and stimulate
food-seeking behavior. Food intake then stimulates secretion of
satiation hormones in the gut including PYY(3-36), oxyntomodulin,
and glucagon-like peptide-1 (GLP-1). These hormones stimulate the
pro-opiomelanocortin/alpha-melanocyte stimulation hormone
(POMC/.alpha.MSH) pathway. The POMC/.alpha.MSH pathway stimulates
different receptors in the cerebral cortex to produce a sensation
of satiation and food reward (Acosta et al., 2014).
[0073] It was recently demonstrated that PYY(3-36) is also present
in both murine and human saliva. In mice, salivary PYY(3-36)
derives from both plasma and is also synthesized in the taste cells
in taste buds of the tongue [2]. Moreover, the cognate receptor,
Y2R, is expressed in the tongue epithelia (Acosta, et al. 2011;
Hurtado et al., 2012). In addition, all other YRs (Y1R, Y4R, and
Y5R) are abundantly expressed in multiple lingual cell types,
including epithelial progenitors, keratinocytes, neuronal dendrites
and taste receptor cells (TRCs) (Hurtado et al., 2012). We showed
that PYY expressed in TRCs modulates responsiveness to
bitter-tasting stimuli and to lipids (La Sala, FASEB, 2013).
[0074] Previous results demonstrated that augmentation of salivary
PYY(3-36) or Exendin-4 result in a decrease in 1-hour food intake
(Acosta et al., 2011). The effect is peptide-specific; similar
studies with neuropeptide Y or amylin resulted in no effect on food
intake. Moreover, it was shown that there is a dose-response
effect. At the lower dose, 0.3 .mu.g/100 g PYY(3-36), treated mice
reduced their caloric intake by 16% as compared to controls.
(PYY(3-36) 3.44.+-.0.06 kcal vs. vehicle 4.10.+-.0.04 kcal, p=0.01)
At the intermediate dose, 3 .mu.g/100 g PYY(3-36), the reduction
was 26%. (PYY(3-36) 3.01.+-.0.06 kcal vs. vehicle 4.10.+-.0.04
kcal, p=0.008). At the higher dose, 10 .mu.g/100 g PYY(3-36), the
caloric intake was further reduced by 42%. (PYY(3-36) 2.36.+-.0.05
kcal vs. vehicle 4.10.+-.0.04 kcal, p=1.81E-06) (Acosta et al.,
2011). However, the doses of PYY used in these studies are
significantly higher than described in aspects herein and could
result in undesired side effects and lack of efficacy (e.g.,
tachiphylaxsis-loss of response at higher doses) in humans.
[0075] The effects of PYY are mediated through the activation of
specific Y2 receptors expressed on the lingual epithelial cells. In
a long-term study involving diet-induced obese (DIO) mice, a
sustained increase in PYY(3-36) was achieved using viral
vector-mediated gene delivery targeting salivary glands (Acosta et
al., 2014). The chronic increase in salivary PYY(3-36) resulted in
a significant long-term reduction in food intake and body weight.
Augmentation of salivary PYY(3-36), while reliably inducing strong
anorexic responses, does not cause taste aversion, a surrogate of
nausea in rodents (Hurtado et al., 2013). Salivary PYY(3-36)
activated forebrain areas known to mediate feeding, hunger, and
satiation while minimally affecting brainstem chemoreceptor zones
that trigger nausea. By comparing neuronal pathways activated by
systemic versus salivary PYY(3-36), a metabolic circuit was
identified associated with Y2R-positive cells on the tongue and
extending through brainstem nuclei into hypothalamic satiety
centers.
[0076] In accordance with aspects disclosed herein, this
alternative circuit regulates ingestive behavior (e.g., promotes a
feeling of fullness over time) without inducing taste aversion.
Aspects described herein provide PYY (e.g., PYY(3-36)) formulations
for the treatment of obesity via direct lingual application and
without concomitant nausea.
TABLE-US-00004 TABLE 2 Dose Escalation Study Study Visit Day DOSE
of PYY(3-36) DOSE PYY(3-36) in 1 ml Day 1 placebo placebo Day 2
2.5xE-6 mg 2.5xE-3 .mu.g Day 4 2.5xE-5 mg 2.5xE-2 .mu.g Day 6
2.5xE-4 mg 2.5xE-1 .mu.g Day 8 2.5xE-3 mg 2.5 .mu.g Day 10 2.5xE-2
mg 25 .mu.g Day 12 2.5xE-1 mg 250 .mu.g Day 14 2.5 mg 2.5 mg
[0077] Table 2 shows an exemplary dose-escalation study from Day 1
through Day 14 with two day intervals between doses after Day 2.
The dose can be prepared, for example, from a stock solution of 2.5
mg/ml PYY(3-36).
[0078] FIG. 1 shows the results of an exemplary study where
PYY(3-36) in 12 subjects. PYY(3-36) was administered to subjects at
the indicated dose (GT-001 Dose on the x-axis), and a feeling of
fullness (mean value on y-axis) was assessed by VAS 30 minutes and
120 minutes after lunch. As shown in FIG. 1, the feeling of
fullness is significantly above placebo level at a dose of 25 ng at
120 minutes post-lunch (VAS score of 7), increases at a dose of 2.5
.mu.g, and reaches about 8 on the VAS scale at a dose of 250
.mu.g.
[0079] FIG. 2 shows the results of an exemplary study where the
feeling of fullness (VAS Fullness (mm)) was plotted against the
time post-treatment (30 min, 60 min, 90 min, and 120 min) with
PYY(3-36) and after the subject ate lunch at four doses (placebo,
25 ng, 25 .mu.g, and 250 .mu.g). As shown in FIG. 2, doses at 25
.mu.g and 250 .mu.g maintain a VAS score of 8 out to 120 minutes
post-lunch. A dose of 25 ng results in a VAS score of about 8 up to
60 minutes post-lunch.
[0080] FIG. 3 shows the normalized concentration in pg/ml of PYY in
the plasma of subjects receiving placebo, 0.25 mg/ml PYY(3-36), and
2.5 mg/ml PYY(3-36) (each followed by lunch) measured in a time
range of up to 4 hours after administration. As shown,
administering the placebo followed by food consumption induces the
known and expected endogenous production of PYY resulting from food
consumption peaking at approximately 20 .mu.g/ml above pre-dose
levels at 1-2 hours post-administration. Administering exogenous
PYY(3-36) to subjects does not raise the level of PYY in plasma
above levels induced by the placebo/meal combination.
[0081] Further aspects provide additional exemplary PYY(3-36)
dosage forms and formulations, including, but not limited to, the
following:
TABLE-US-00005 TABLE 3 Oral Film Strip Strength (label claim)
Component and Quantity Quality per unit Standard Function (mg) %
PYY.sub.3-36, human Drug substance 2.5 ng to 5 .times. 10.sup.-7 to
0.5 2.5 mg Carboxmethylcellulose Polymer 225 45 Polyethylene glycol
Plasticizer 100 20 Eugradit RL-100 Polymer 94.5 18.9 Polysorbate 20
Surfactant 25 5 Aspartame Sweetening 15 3 agent Citric acid Saliva
15 3 stimulating agent, preservative FD&C Blue No. 2 Color 0.5
0.1 Aluminum Lake Peppermint Flavor 10 2 Ethanol Solvent -- --
Purified Water Solvent -- -- Total 500 100
[0082] Solvents are removed during manufacture.
[0083] Further aspects provide exemplary oral film strip dosage
forms as shown in Table 3. In one aspect, oral film strip
pharmaceutical compositions comprising about 2.5 ng 2.5 mg of
PYY(3-36) are provided. In this aspect, the oral film strip
pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250
ng, and 2.5 .mu.g of PYY(3-36). In another aspect, the oral film
strip pharmaceutical composition further comprises a suitable
polymer, plasticizer, sweetening agent, saliva stimulating agent,
preservative, and optional coloring, flavorings, and solvents. See
e.g., Bala, et. al., Orally dissolving strips: A new approach to
oral drug delivery system, Int J Pharm Investig. 2013 April-June;
3(2): 67-76; Tomar, Formulation and Evaluation of Fast Dissolving
Oral Film of Dicyclomine as potential route of Buccal Delivery,
International Journal of Drug Development & Research April-June
2012 Vol. 4 Issue 2 ISSN 0975-9344.
TABLE-US-00006 TABLE 4 Troche Strength (label claim) Component and
Quantity Quality per unit Standard Function (mg) % PYY.sub.3-36,
human Drug substance 2.5 ng to 2.0 .times. 10.sup.-7 to 0.2 2.5 mg
Polyethylene glycol Vehicle or Base 963.8 79 Acacia Suspending 183
15 agent Stevia Sweetener 36.6 3 Peppermint Flavor 24.4 2 Total
1220 100
[0084] Further aspects provide exemplary troche dosage forms as
shown in Table 4. In one aspect, troche pharmaceutical compositions
comprising about 2.5 ng 2.5 mg of PYY(3-36) are provided. In this
aspect, the troche pharmaceutical composition can comprise about
2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g of PYY(3-36). In one aspect,
the troche dosage form comprises PYY(3-36), a vehicle or base, and
a suspending agent.
[0085] In these aspects, the suspending agent, sweetener, and
flavoring components are optional. In another aspect, the vehicle
or base of the troche can be sugar, made adhesive by admixture with
acacia or tragacanth, fruit paste (e.g., made from black or red
currants), confection of rose, or balsam of tolu. See, e.g., Kamini
et al., Formulation and Percentage Evaluation of Gum-Acacia as A
Binder W. S. R. to Jwaraghani Gutika (Herbo-Mineral Preparation,
Int J Res Med. 2016; 5(1); 21-24 (2016).
TABLE-US-00007 TABLE 5 Lollipop Strength (label claim) Component
and Quantity Quality per unit Standard Function (mg/mL) %
PYY.sub.3-36, human Drug substance 2.5 ng to 1.25 .times. 10.sup.-7
to 0.125 2.5 mg EMDEX (hydrated Filler, 1640 82 dextrose (dextrose
Sweetener monohydrate) containing about 7% maltodetrin Disodium
hydrogen Buffer 16 0.8 phosphate Citric acid Preservative 10 0.5
Raspberry Flavor 4 0.2 Confectionary sugar Filler, 310 15.5
Sweetener Magnesium stearate Lubricant 20 1 Total 2000 mg 100
[0086] Further aspects provide exemplary lollipop dosage forms as
shown in Table 5. In one aspect, lollipop pharmaceutical
compositions can comprise about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the lollipop pharmaceutical composition
comprises about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g of PYY(3-36).
In one aspect, the lollipop dosage form comprises PYY(3-36), a
filler, buffer, lubricant and a preservative. Flavoring, sweetener,
are optional components. In another aspect, the lollipop dosage
form further comprises maltose-dextrose, water, and cornstarch or
another binding material. In another aspect, the lollipop dosage
form further comprises maltose-dextrose, water, and cornstarch or
another binding material. See, e.g., US Patent Application
Publication 2007/0104763.
TABLE-US-00008 TABLE 6 Chewing Gum Strength (label claim) Component
and Quantity Quality per unit Standard Function (mg/mL) %
PYY.sub.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25 2.5 mg Compressible Gum Gum base 883 88.3 Base Powder
(e.g., Health in Gum .RTM.) Sorbitol Granulating 100 10 agent,
Sweetener Magnesium stearate Lubricant 10 1 Citric acid
Preservative, 5 0.5 salivating agent Peppermint Flavor 2 0.2 Total
1000 mg 100
[0087] Further aspects provide exemplary chewing gum dosage forms
as shown in Table 6. In one aspect, chewing gum pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the chewing gum pharmaceutical
composition can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g
of PYY(3-36). In one aspect, the chewing gum dosage form comprises
PYY(3-36), a gum base, a granulating agent, a lubricant, a
preservative, and a lubricant. Flavoring, and sweeteners are
optional components. See, e.g., Aslani, et al., Medicated chewing
gum, a novel drug delivery system, J. Res Med Sci. 2015 April;
20(4): 403-411. Alternatively, chewing gum dosage forms can be made
by direct compression. See, e.g., U.S. Pat. No. 7,208,186. See,
also, Heema et. al., Medicated chewing gums-updated review. Int J
Pharm Res Dev. 2010; 2:66-76.
[0088] Further aspects provide spray-dried particle dosage forms
(e.g., sachet of spray-dried particles) as shown in Tables 7-9. In
these aspects, pharmaceutical compositions comprising about 2.5 ng
2.5 mg of PYY(3-36) are provided. The exemplary spray-dried
pharmaceutical composition comprises about 2.5 ng, 25 ng, 250 ng,
and 2.5 .mu.g of PYY(3-36).
TABLE-US-00009 TABLE 7 Spray-Dried Particles, Example 1 Strength
(label claim) Component and Quantity Quality per unit Standard
Function (mg/mL) % PYY.sub.3-36, human Drug substance 2.5 ng to 2.5
.times. 10.sup.-7 to 0.25 2.5 mg Anhydrous .alpha. Caarrier 800 80
Lactose Sorbitol Granulating 93 10 agent, Sweetener Disodium
Hydrogen Buffer 100 10 Phosphate Potassium Sorbate, Preservative 5
0.5 NF Flavor Flavor 2 0.2 Purified Water Solvent/ -- -- suspending
solution Total 1000 mg 100
[0089] Solvent is removed during manufacture.
[0090] In the aspect of Table 7, a drug (e.g., PYY(3-36) can be
mixed with excipients into a solution or suspension, and sprayed to
form a particle. For example, PYY(3-36) and the excipients of Table
7 can be combined with lactose in solution or suspension and
spray-dried followed by collection of particles on a filter. See,
e.g., Luhn, Using Excipients In Powder Formulations, Pharmaceutical
Technology Europe, Vol. 23, Issue 1 (Jan. 7, 2011); Wu et al.,
Studies on the spray dried lactose as carrier for dry powder
inhalation, Asian Journal of Pharmaceutical Sciences 9 (2014)
336-341.
TABLE-US-00010 TABLE 8 Spray-Dried Particles-Example 2 Strength
(label claim) Component and Quantity Quality per unit Standard
Function (mg/mL) % PYY.sub.3-36, human Drug substance 2.5 ng to 2.5
.times. 10.sup.-7 to 0.25 2.5 mg Spray-dried Lactose Filler 800 80
Monohydrate Sorbitol Granulating 93 9.3 agent, Sweetener Disodium
Hydrogen Buffer 100 10 Phosphate Potassium Sorbate, Preservative 5
0.5 NF Flavor Flavor 2 0.2 Purified Water Solvent/ -- -- suspending
solution Total 1000 mg 100
[0091] Solvent is removed during manufacture.
[0092] In the aspect of Table 8, the drug and excipients can be wet
granulated with commercially available spray dried lactose and then
dried. See, e.g., Huang et al., Using spray-dried lactose
monohydrate in wet granulation method for a low-dose oral
formulation of a paliperidone derivative, Powder Technology 246
(2013) 379-394. In one aspect, the dosage form can be a filled
sachet of spray dried particles.
TABLE-US-00011 TABLE 9 Spray-Dried Particles-Example 3 Strength
(label claim) Component and Quantity Quality per unit Standard
Function (mg/mL) % PYY.sub.3-36, human Drug substance 2.5 ng to 2.5
.times. 10.sup.-7 to 0.25 2.5 mg Anhydrous .alpha. Carrier 800 80
Lactose Sorbitol Granulating 93 9.3 agent, Sweetener Disodium
Hydrogen Buffer 100 10 Phosphate Potassium Sorbate, Preservative 5
0.5 NF Flavor Flavor 2 0.2 Purified Water Solvent/ -- -- suspending
solution Total 1000 mg 100
[0093] Solvent is removed during manufacture.
[0094] In the aspect of Table 9, the drug and excipients can be
sprayed onto commercially available lactose or pre-step spray dried
lactose, as described. Asian Journal of Pharmaceutical Sciences 9
(2014) 336-341.
[0095] In another aspect, the spray-dried particles from, for
example, Tables 7-9, can be delivered in dry powder inhaler
(propellant). In one aspect, the size of the spray-dried particles
is between 1 to 10 microns to avoid blocking the orifice of the
inhaler device, yet, for example, large enough to be less likely to
be inhaled and to be mostly deposited in the mouth. In this aspect,
the propellant can be HFA 134a or HFA 227, or a combination of the
two. The nozzle design on the inhaler could be adapted to
facilitate actuation of a dose to the tongue. In yet another
aspect, spray-dried particles could be delivered without propellant
(e.g., using a unit dose delivery device such as the Aptar pharma
UDS device).
[0096] Further aspects provide microporous polysaccharide
microsphere dosage forms.
TABLE-US-00012 TABLE 10 Frozen Particles Strength (label claim)
Component and Quantity Quality per unit Standard Function (mg/mL) %
PYY.sub.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25 2.5 mg Spray-dried Lactose Filler 800 80 Monohydrate
Sorbitol Granulating 93 9.3 agent, Sweetener Disodium Hydrogen
Buffer 100 10 Phosphate Potassium Sorbate, Preservative 5 0.5 NF
Flavor Flavor 2 0.2 Purified Water Solvent/ QS to QS to suspending
1000 mL 100 solution Total 1000 mg 100
[0097] Further aspects provide exemplary frozen particle dosage
forms as shown in Table 10. In one aspect, frozen particle
pharmaceutical compositions comprising about 2.5 ng 2.5 mg of
PYY(3-36) are provided. In this aspect, the frozen particle
pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250
ng, and 2.5 .mu.g of PYY(3-36). In this aspect, the pharmaceutical
compositions comprise PYY(3-36), a filler, a granulating agent, a
buffer, a preservative, and a solvent/suspending agent. Optional
sweeteners and flavorings can be added. In this aspect, the wet
granulation method described above with respect to Table 8 can be
used. However, instead of a drying step, the particles can be
filled into sachets of frozen particles and frozen.
[0098] Alternatively, a frozen PYY(3-36) solution (Table 11, below)
can be used to fill tubes prior to freezing. Any suitable tube can
be used (e.g., polypropylene tubes used generally for
pharmaceuticals, cosmetics, and food). The tube can be flexible to
permit the frozen solution to be dispensed on to the tongue and
thawed slowly, for example. In yet another aspect, the frozen
solution can be used in a "blow, fill, seal" dosage form and
dispensed in a manner similar to an eye drop or mouthwash
dispenser. Markarian, "Blow-fill-seal Technology Advances in
Aseptic Filling Applications: New advanced aseptic manufacturing
technologies are available for filling liquid pharmaceuticals,
including biologics, Equipment and Processing Report, Jun. 18,
2014.
TABLE-US-00013 TABLE 11 Frozen Solution Strength (label claim)
Component and Quantity Quality per unit Standard Function (mg/mL) %
PYY.sub.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25 2.5 mg Sorbitol Granulating 100 10 agent, Sweetener
Disodium Hydrogen Buffer 100 10 Phosphate Potassium Sorbate,
Preservative 5 0.5 NF Flavor Flavor 2 0.2 Polyethylene Stabilizer
100 10 Glycol 8000 Purified Water Solvent/ QS to QS to suspending 1
mL 100 solution
TABLE-US-00014 TABLE 12 Lyophilized Particles Strength (label
claim) Component and Quantity Quality per unit Standard Function
(mg) % PYY.sub.3-36, human Drug substance 2.5 ng to 5.0 .times.
10.sup.-6 to 5.0 2.5 mg Trehalose Cryoprotectant/ 25.5 to 28 51 to
56 Stabilizer Edetate Disodium, Antioxidant 1 2.0 Dihydrate, USP
Sodium Phosphate, Buffer 3 6.0 Monobasic, Dihydrate, USP Potassium
Sorbate, Preservative 2 0.20 NF Hydrochloric Acid pH modifier QS to
pH -- (HCl), NF, USP 7.0 .+-. 0.1 Sodium Hydroxide pH modifier QS
to pH -- (NaOH), USP 7.0 .+-. 0.1 Purified Water Solvent -- --
[0099] Solvent is removed during manufacture. Diluent can be
sterile water or dextrose 5%.
[0100] Further aspects provide exemplary lyophilized particle
dosage forms as shown in Table 12. In one aspect, lyophilized
particle pharmaceutical compositions comprising about 2.5 ng 2.5 mg
of PYY(3-36) are provided. In this aspect, the lyophilized particle
pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250
ng, and 2.5 .mu.g of PYY(3-36). In this aspect, the pharmaceutical
compositions comprise PYY(3-36), a cryoprotectant/stabilizer, an
antioxidant, a buffer, preservative(s), optional pH modifiers, and
a solvent.
[0101] In one aspect, the lyophilized particles are separated from
the diluent in a pre-filled oral syringe with mixing chamber. See,
e.g., Vetter-Pharma, Vetter Dual Chamber Systems Website
Description. In another aspect, the lyophilized particles are
separated from the diluent with a mixing chamber.
TABLE-US-00015 TABLE 13 Oral Spray Strength (label claim) Component
and Quantity Quality per unit Standard Function (mg) %
PYY.sub.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25% 2.5 mg Aspartame Sweetening 30 3 agent Edetate Disodium,
Antioxidant 20 2.0 Dihydrate, USP Sodium Phosphate, Buffer 60 6.0
Monobasic, Dihydrate, USP Potassium Sorbate, Preservative 2 0.20 NF
Peppermint Flavor 10 1 Hydrochloric Acid pH modifier QS to pH --
(HCl), NF, USP 7.0 .+-. 0.1 Sodium Hydroxide pH modifier QS to pH
-- (NaOH), USP 7.0 .+-. 0.1 Purified Water Solvent QS to QS to 1 mL
100
[0102] Further aspects provide exemplary oral spray dosage forms as
shown in Table 13. In one aspect, oral spray pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the oral spray pharmaceutical composition
can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g of
PYY(3-36). In this aspect, the pharmaceutical compositions comprise
PYY(3-36), an antioxidant, a buffer, a preservative, a solvent,
optional pH modifiers, and optional flavorings and sweetener
agents.
[0103] In another aspect, the oral spray can be one device (CCS
with activator), an oral spray with vial adaptor for actuator at
the time of administration, an oral spray solution to be poured
into a device with an actuator, an oral solution in a prefilled
oral syringe, an oral solution in a blow-filled sealed tube, an
oral solution in vial or tube with a measuring device (e.g.,
dropper, syringe), or a small squeeze bottle that dispenses drops
(e.g., similar to an optical solution).
TABLE-US-00016 TABLE 14 Softgel Capsule Strength (label claim)
Component and Quantity Quality per unit Standard Function (mg) %
PYY.sup.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25% 2.5 mg Gelatin A Shell 440 44 Glycerin Base 40 4 Sorbitol
Sweetening 100 10 Agent Polyethylene Base 30 3 Glycol 400
Peppermint Flavor 20 2 Potassium Sorbate, Preservative 2 0.2 NF
Color Color 1.5 0.15 Purified Water Solvent QS to QS to 1 mL
100
[0104] Further aspects provide exemplary softgel capsule dosage
forms as shown in Table 14. In one aspect, softgel capsule
pharmaceutical compositions comprising about 2.5 ng 2.5 mg of
PYY(3-36) are provided. In this aspect, the softgel capsule
pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250
ng, and 2.5 .mu.g of PYY(3-36). In this aspect, the pharmaceutical
compositions comprise PYY(3-36), a shell (e.g., gelatin), a base
(e.g., glycerin), a second base (polyethylene glycol), a
preservative, a solvent, optional flavorings, coloring, and
sweetener agents. In another aspect, the softgel capsule can have a
removable nib to open the capsule and pour the contents on to the
tongue.
TABLE-US-00017 TABLE 15 Mouthwash Strength (label claim) Component
and Quantity Quality per unit Standard Function (mg) %
PYY.sub.3-36, human Drug substance 2.5 ng to 2.5 .times. 10.sup.-7
to 0.25% 2.5 mg Sucralose Sweetening 30 3 agent Edetate Disodium,
Antioxidant 20 2.0 Dihydrate, USP Glycerin Solvent 80 8.0 95%
ethanol Solvent, 100 10.0 preservative Peppermint Flavor 200 20
PEG-40 Sorbitan Surfactant 400 40.0 Diisosterate Purified Water
Solvent QS to QS to 1 mL 100
[0105] Further aspects provide exemplary mouthwash dosage forms as
shown in Table 15. In one aspect, mouthwash pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the mouthwash pharmaceutical composition
can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g of
PYY(3-36). In this aspect, the pharmaceutical compositions comprise
PYY(3-36), an antioxidant, a surfactant, a preservative, and a
solvent(s). Optional flavorings and sweeteners may also be
added.
TABLE-US-00018 TABLE 16 Buccal Tablets-Example 1 Strength (label
claim) Component and Quantity Quality per unit Standard Function
(mg/mL) % PYY.sub.3-36, human Drug substance 2.5 ng to 1.7 .times.
10.sup.-6 to 1.7 2.5 mg Hydroxypropyl Binder/ 10 6.7
methylcellulose Mucoadhesive (HPMC) 15 cps Mannitol Sweetener/ 40
26.7 Diluent Carbopol 934P Mucoadhesive 10 6.7 Aspartame Sweetener
3 2.0 Sodium stearyl, Lubricant 3 2.0 fumarate (SSF) Spray-dried
flavor Flavor 3 2.0 agent Polyvinyl Dispersant/ 6 4.0 pyrrolidone,
K30 mucoadhesive Ethyl cellulose Filler/Binder/ 72.5 to 75 48.3 to
50.0 Viscosity Enhancer/ Mucoadhesive Total 150 100
[0106] Further aspects provide exemplary buccal tablet dosage forms
as shown in Table 16. In one aspect, buccal tablet pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the buccal tablet pharmaceutical
composition can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g
of PYY(3-36). In this aspect, the pharmaceutical compositions
comprise PYY(3-36), mucoadhesive(s), a dispersant, a preservative,
a lubricant, and fillers or binders. Optional flavorings and
sweeteners may also be added. See, e.g., Shirsand et. al.,
Formulation and optimization of mucoadhesive bilayer buccal tablets
of atenolol using simplex design method, Int J Pharm Investig. 2012
January-March; 2(1): 34-41.
TABLE-US-00019 TABLE 17 Buccal Tablets-Example 2 Strength (label
claim) Component and Quantity Quality per unit Standard Function
(mg) % PYY.sub.3-36, human Drug substance 2.5 ng to 2.1 .times.
10.sup.-6 to 2.1 2.5 mg Hydroxypropyl Binder/ 30 25 methylcellulose
Mucoadhesive K4M Carbopol 934P Mucoadhesive 5 4.2 Xantham gum
Mucoadhesive 30 25 Lactose Diluent/Filler/ 51.3 to 53.8 42.8 to
44.8 Binder Magnesium Stearate Lubricant 1.2 1.0 Total 120 100
[0107] Further aspects provide exemplary buccal tablet dosage forms
as shown in Table 17. In one aspect, buccal tablet pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the buccal tablet pharmaceutical
composition can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g
of PYY(3-36). In this aspect, the pharmaceutical compositions
comprise PYY(3-36), mucoadhesive(s), a lubricant, and diluents,
fillers or binders. See, e.g., Chaudhari et al., Formulation and
Evaluation of Buccal Tablet of Salbutamol Sulphate, IRJP 2011, 2
(12), 238-242.
TABLE-US-00020 TABLE 18 Lyophilized Tablet Strength (label claim)
Component and Quantity Quality per unit Standard Function (mg) %
PYY.sub.3-36, human Drug substance 2.5 ng to 5.0 .times. 10.sup.-6
to 5.0 2.5 mg Polyvinyl pyrrolidone Mucoadhesive 2.5 5.0 Carbopol
934P Mucoadhesive 5 10 Trehalose Cryoprotectant/ 25.5 to 28 51 to
56 Stabilizer Edetate Disodium, Antioxidant 1 2.0 Dihydrate, USP
Sodium Phosphate, Buffer 3 6.0 Monobasic, Dihydrate, USP
Polysorbate, 20, NF Surfactant 3 6.0 Hydrochloric Acid pH modifier
QS to pH -- (HCl), NF, USP 7.0 .+-. 0.1 Sodium Hydroxide pH
modifier QS to pH -- (NaOH), USP 7.0 .+-. 0.1 Sterile Water for
Solvent -- -- Injection, USP
[0108] Solvent Removed During Manufacturing
[0109] Further aspects provide exemplary lyophilized tablet dosage
forms as shown in Table 18. In one aspect, lyophilized tablet
pharmaceutical compositions comprising about 2.5 ng-2.5 mg of
PYY(3-36) are provided. In this aspect, the lyophilized tablet
pharmaceutical composition can comprise about 2.5 ng, 25 ng, 250
ng, and 2.5 .mu.g of PYY(3-36). In this aspect, the pharmaceutical
compositions comprise PYY(3-36), mucoadhesive(s), a surfactant, a
cryoprotectant/stabilizer, an antioxidant, and pH modifiers and
solvent.
TABLE-US-00021 TABLE 19 Oral Dissolving Tablet ("ODT") Strength
(label claim) Component and Quantity Quality per unit Standard
Function (mg) % PYY.sub.3-36, human Drug substance 2.5 ng to 5
.times. 10.sup.-7 to 1.0 2.5 mg Microcrystaline Binder 100 40
cellulose Mannitol Binder 119.75 45.9 Crospovidone Disintegrant 25
10 Aspartame Sweetening 5 2 agent FD&C Blue No. 2 Color 0.25
0.1 Aluminum Lake Peppermint Flavor 1.25 0.5 Magnesium stearate
Lubricant 1.25 0.5 Total 250 100
[0110] Further aspects provide exemplary ODT tablet dosage forms as
shown in Table 19. In one aspect, ODT tablet pharmaceutical
compositions comprising about 2.5 ng 2.5 mg of PYY(3-36) are
provided. In this aspect, the ODT tablet pharmaceutical composition
can comprise about 2.5 ng, 25 ng, 250 ng, and 2.5 .mu.g of
PYY(3-36). In this aspect, the pharmaceutical compositions comprise
PYY(3-36), binder(s), a disintegrant, a lubricant, and optional
sweetening agents, flavorings, and lubricants.
[0111] In one aspect, the ODT tablet dosage form is a blended
powder system that is subsequently compressed into tablets using
standard rotary press, and packaged into blister packs or bottles
depending on the friability of the tablets. Finished tablets can
have a disintegration time of 30 seconds or less on the tongue, for
example. Flavoring, coloring, and sweetener levels can be varied as
required for end-user experience.
[0112] The compositions described herein can be used to treat a
patient in need of treatment as described herein. The terms
"treat," "prevent," or similar terms, as used herein, do not
necessarily mean 100% or complete treatment or prevention. Rather,
these terms refer to various degrees of treatment or prevention of
a particular disease (e.g., 100%, 90%, 80%, 70%, 60%, 50%, 40%,
30%, 20%, 10%, 5%, or 1%) as recognized in the art as being
beneficial. The terms "treatment" or "prevention" also refer to
delaying onset of a disease for a period of time or delaying onset
indefinitely. The term "treatment" or "treating" refers to
administering a drug or treatment to a patient or prescribing a
drug to a patient where the patient or a third party (e.g.,
caretaker, family member, or health care professional) administers
the drug or treatment.
[0113] The components of the compositions described herein also
encompass derivatives and analogs. In one embodiment, the terms
"derivative" or "analogs" include, but are not limited to, ether
derivatives, acid derivatives, amide derivatives, ester derivatives
and the like. Methods of preparing these derivatives are known to a
person skilled in the art. For example, ether derivatives are
prepared by the coupling of the corresponding alcohols. Amide and
ester derivatives are prepared from the corresponding carboxylic
acid by a reaction with amines and alcohols, respectively.
[0114] Any suitable dosage form can be used for delivery of the
pharmaceutical compositions described herein in addition to dosage
forms and formulations described above. In one aspect, the dosage
form is especially suitable for intraoral or oromucosal delivery.
In another aspect, the dosage form is a lozenge (e.g., planar
sheet, solid or semi-solid candy). In another aspect, the dosage
form is a gel, cream, foam, orally disintegrating tablets, or
paste. The lozenge can comprise dissolvable material. In another
aspect, the dosage form comprises chewing gum. In yet another
aspect, the dosage form is a liquid formulation (e.g., emulsion,
syrup, elixir, suspension, or a solution, gargles, mouthwashes,
gingival solutions, oromucosal solutions and oromucosal
suspensions, semi-solid oromucosal preparations (including for
example gingival gel, gingival paste, oromucosal gel, oromucosal
paste), oromucosal drops, oromucosal sprays and sublingual sprays
(including oropharyngeal sprays), lozenges and pastilles,
compressed lozenges, sublingual tablets and buccal tablets,
oromucosal capsules, mucoadhesive preparations.). In a further
aspect, the liquid formulation is a spray or drops for oral
administration.
[0115] In one aspect, compositions described herein, or a thereof
can be compounded or used as a starting material for compounding
with a physiologically acceptable vehicle, carrier, excipient,
binder, preservative, stabilizer, flavor, etc., in a unit dosage
form as called for by accepted pharmaceutical practice. The amount
of active substance in compositions or preparations (e.g., active
pharmaceutical ingredients) comprising the components of
compositions described herein is such that a suitable dosage in the
range indicated is obtained, as described herein.
[0116] In another aspect, the components of compositions described
herein can be formulated in a unit dosage form. The term "unit
dosage from" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each unit
containing a predetermined quantity of active material calculated
to produce the desired therapeutic effect, in association with one
or more suitable pharmaceutical excipients.
[0117] In one aspect, one or more of the components of compositions
described herein are mixed with or used as starting materials mixed
with a suitable pharmaceutically acceptable carrier to form
compositions, for example, as described herein. Upon mixing or
addition of the compound(s), the resulting mixture may be a
solution, suspension, emulsion, or the like. Liposomal suspensions
may also be used as pharmaceutically acceptable carriers. These may
be prepared according to methods known to those skilled in the art.
The form of the resulting mixture depends upon a number of factors,
including the intended mode of administration and the solubility of
the compound in the selected carrier or vehicle. In one aspect, the
effective concentration is sufficient for lessening or ameliorating
at least one symptom of the disease, disorder, or condition treated
and may be empirically determined.
[0118] Pharmaceutical carriers or vehicles suitable for
administration of the components of compositions described herein
include any such carriers suitable for the particular mode of
administration. In addition, the active materials can also be mixed
with other active materials that do not impair the desired action,
or with materials that supplement the desired action, or have
another action. The compounds may be formulated as the sole
pharmaceutically active ingredient in the composition or may be
combined with other active ingredients.
[0119] In another aspect, if the components of compositions
described herein exhibit insufficient solubility, methods for
solubilizing may be used. Such methods are known and include, but
are not limited to, using co-solvents such as dimethylsulfoxide
(DMSO), using surfactants such as TWEEN (e.g., polysorbate), and
dissolution in aqueous sodium bicarbonate.
[0120] The concentration of the compound is effective for delivery
of an amount upon administration that lessens or ameliorates at
least one symptom of the disorder for which the compound is
administered. Typically, the compositions are packaged for unit
dosage administration.
[0121] In another aspect, the components of compositions described
herein may be prepared with carriers that protect them against
rapid elimination from the body, such as time-release formulations
or coatings. Such carriers include controlled release formulations,
such as, but not limited to, microencapsulated delivery systems.
The active compound can be included in the pharmaceutically
acceptable carrier in an amount sufficient to exert a
therapeutically useful effect in the absence of undesirable side
effects on the patient treated. The therapeutically effective
concentration may be determined empirically by testing the
compounds in known in vitro and in vivo model systems for the
treated disorder.
[0122] In another aspect, the components of compositions described
herein can be enclosed in multiple or single dose containers. The
enclosed compounds and compositions can be provided in kits, for
example, including component parts that can be assembled for use.
For example, one or more of the compounds (e.g., PYY, PYY(3-36), or
analogs) can be used as a starting material for a lyophilized form
(e.g., lyophilized oral dissolving tablet) and a suitable diluent
may be provided as a separated component for combination prior to
use. A kit may include components of compositions described herein
and a second or third therapeutic agent for co-administration. The
components of compositions described herein and the second or third
therapeutic agent may be provided as separate component parts. A
kit may include a plurality of containers, each container holding
one or more unit dose of the components of compositions described
herein. In one aspect, the containers can be adapted for the
desired mode of administration, including, but not limited to
tablets, gel capsules, sustained-release capsules, and the like for
oral administration; depot products, pre-filled syringes, ampoules,
vials, and the like for parenteral administration; and patches,
medipads, creams, and the like for topical administration.
[0123] In yet another aspect, the dosage form is lyophilized oral
dissolving tablets. The lyophilized oral dissolving tablets can be
modified with the addition of sugars to produce, for example, a
higher Tg Add in lyophilized oral dissolving tablets these can
include sugars that produce Tg (glass transition temperature)
higher than room temperature. See, e.g., Elnggar et al.,
Maltodextrin: A Novel Excipient Used in Sugar-Based Orally
Disintegrating Tablets and Phase Transition Process, AAPS Pharm Sci
Tech. 2010 June; 11(2): 645-651 (Apr. 20, 2010).
[0124] The concentration of the components of compositions
described herein will depend on dissolution, absorption,
metabolism, and excretion rates of the active compound(s), the
dosage schedule, and amount administered as well as other factors
known to those of skill in the art.
[0125] In another aspect, the active ingredients may be
administered at once, or may be divided into a number of smaller
doses to be administered at intervals of time. It is understood
that the precise dosage and duration of treatment is a function of
the disease being treated and may be determined empirically using
known testing protocols or by extrapolation from in vivo or in
vitro test data. It is to be noted that concentrations and dosage
values may also vary with the severity of the condition to be
alleviated. It is to be further understood that for any particular
subject, specific dosage regimens should be adjusted over time
according to the individual need and the professional judgment of
the person administering or supervising the administration of the
compositions, and that the concentration ranges set forth herein
are exemplary only and are not intended to limit the scope or
practice of the claimed compositions.
[0126] If oral administration is desired, the compound can be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can be
formulated in an enteric coating that maintains its integrity in
the stomach and releases the active compound in the intestine. The
composition may also be formulated in combination with an antacid
or other such ingredient.
[0127] Oral compositions will generally include an inert diluent or
an edible carrier and may be optionally lyophilized and compressed
into tablets or enclosed in gelatin capsules. For the purpose of
oral therapeutic administration, the active compound or compounds
can be incorporated with excipients and used in the form of
tablets, capsules, or troches. Pharmaceutically compatible binding
agents and adjuvant materials can be included as part of the
composition.
[0128] The tablets, pills, capsules, troches, and the like can
contain any of the following ingredients or compounds of a similar
nature: a binder such as, but not limited to, gum tragacanth,
acacia, corn starch, or gelatin; an excipient such as
microcrystalline cellulose, starch, or lactose; a disintegrating
agent such as, but not limited to, alginic acid and corn starch; a
lubricant such as, but not limited to, magnesium stearate; a
glidant, such as, but not limited to, colloidal silicon dioxide; a
sweetening agent such as sucrose or saccharin; and a flavoring
agent such as peppermint, methyl salicylate, or fruit
flavoring.
[0129] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials, which modify the physical form of the dosage unit, for
example, coatings of sugar and other enteric agents. The compounds
can also be administered as a component of an elixir, suspension,
syrup, wafer, chewing gum or the like. A syrup may contain, in
addition to the active compounds, sucrose as a sweetening agent and
certain preservatives, dyes and colorings, and flavors.
[0130] The active materials can also be mixed with other active
materials that do not impair the desired action, or with materials
that supplement the desired action. The components of compositions
described herein can be used, for example, in combination with an
anti-obesity, anti-diabetes, or similar drug (e.g., lorcaserin,
orlistat, phentermine/topiramate, sibutramine, rimonabant,
metformin, exenatide, liraglutide, pamlintide, naltrexone, and
tesofensine).
[0131] In one aspect, solutions or suspensions used for parenteral,
pump delivery, intradermal, subcutaneous, or topical application
can include any of the following components: a sterile diluent such
as water for injection, saline solution, fixed oil, a naturally
occurring vegetable oil such as sesame oil, coconut oil, peanut
oil, cottonseed oil, and the like, or a synthetic fatty vehicle
such as ethyl oleate, and the like, polyethylene glycol, glycerin,
propylene glycol, or other synthetic solvent; antimicrobial agents
such as benzyl alcohol and methyl parabens; antioxidants such as
ascorbic acid and sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid (EDTA) or its disodium salt;
buffers such as acetates, citrates, and phosphates; and agents for
the adjustment of tonicity such as sodium chloride and dextrose.
Parenteral preparations can be enclosed in ampoules, disposable
syringes, or multiple dose vials made of glass, plastic, or other
suitable material. Buffers, preservatives, antioxidants, and the
like can be incorporated as required.
[0132] Where administered intravenously, suitable carriers include,
but are not limited to, physiological saline, phosphate buffered
saline (PBS), and solutions containing thickening and solubilizing
agents such as glucose, polyethylene glycol, polypropylene glycol,
and mixtures thereof. Liposomal suspensions including
tissue-targeted liposomes may also be suitable as pharmaceutically
acceptable carriers. These may be prepared according to methods
known in the art.
[0133] In another aspect, the components of compositions described
herein may be prepared with carriers that protect the compound
against rapid elimination from the body, such as time-release
formulations or coatings. Such carriers include controlled release
formulations, such as, but not limited to, implants and
microencapsulated delivery systems, and biodegradable,
biocompatible polymers such as collagen, ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, polyorthoesters, polylactic
acid, hydroxyl propyl methyl cellulose (HPMC), other cellulose
derivatives, and the like. Methods for preparation of such
formulations are known to those skilled in the art.
[0134] In yet another aspect, compounds employed in the methods of
the disclosure may be administered enterally or parenterally. When
administered orally, compounds employed in the methods of the
disclosure can be administered in usual dosage forms for oral
administration as is well known to those skilled in the art. These
dosage forms include the usual solid unit dosage forms of tablets
and capsules as well as liquid dosage forms such as solutions,
suspensions, and elixirs. When the solid dosage forms are used,
they can be of the sustained release type so that the compounds
employed in the methods described herein need to be administered
only once or twice daily.
[0135] The oral dosage forms can be administered to the patient 1,
2, 3, or 4 times daily, or as needed. The components of
compositions described herein can be administered either three or
fewer times, or even once or twice daily. Whatever oral dosage form
is used, it can be designed so as to protect the compounds employed
in the methods described herein from the acidic environment of the
stomach. Enteric coated tablets and capsules filled with small
spheres, each coated to protect from the acidic stomach, are also
well known to those skilled in the art and can be used with aspects
described herein.
[0136] The terms "therapeutically effective amount" and
"therapeutically effective period of time" are used to denote
treatments at dosages and for periods of time effective to treat,
ameliorate, or reduce conditions or symptoms described herein.
[0137] One of skill in the art will appreciate that such
therapeutic effect resulting in a lower effective concentration of
the components of compositions described herein may vary
considerably depending on the tissue, organ, or the particular
animal or patient to be treated. It is also understood that while a
patient may be started at one dose, that dose may be varied
overtime as the patient's condition changes.
[0138] It should be apparent to one skilled in the art that the
exact dosage and frequency of administration will depend on the
particular compounds employed in the methods of the disclosure
administered, the particular condition being treated, the severity
of the condition being treated, the age, weight, general physical
condition of the particular patient, and other medication the
individual may be taking as is well known to administering
physicians who are skilled in this art.
EXAMPLES
Example 1--PYY(3-36) Dose Escalation Study
[0139] Day 1 (Check into Study Unit and Placebo Administration)
[0140] Subjects who complete all screening procedures and meet all
inclusion and exclusion criteria described within the protocol and
found to be eligible for study enrollment checked into the Study
Unit (i.e., the study facility). The morning of the study,
participants fasted prior to arriving at the SU. Participants
fasted for at least 12 hours prior to Day 1 of the study.
Participants were permitted to only drink water prior to arrival to
SU and were able to brush their teeth. The following assessments
and measurements were taken:
[0141] (1) Inspection of the lingual mucosa.
[0142] (2) Updating medical and medication history prior to placebo
application.
[0143] (3) Assessing health status. If participant has either
rhinitis or gastrointestinal distress, the participant will be
discontinued for that day.
[0144] (4) Measuring body weight and BMI.
[0145] (5) Measuring vital signs (BP, HR, and body temperature). BP
and HR were measured twice in the sitting position and twice in the
standing position. If BP was high at baseline sitting (>160
systolic), BP was re-checked after participant was sitting for 5-10
min. Body temperature was measured once.
[0146] (6) Performing urine drug screen, urine cotinine test,
alcohol breath test, and urine pregnancy test.
[0147] (7) Subjects provided a 325-400 calorie breakfast and
calorie intake was recorded.
[0148] (8) Water was provided "ad-libitum" and volume recorded.
[0149] (9) Four (4) hours post breakfast, the VAS for Appetite and
Satiety was performed.
[0150] (10) Inserting a cannula to obtain blood samples, obtaining
a 5 ml blood sample, and screening for anti-GT-001 antibodies.
[0151] (11) Obtaining a fasting PK blood sample #1 (5 ml) 15
minutes prior to placebo.
[0152] (12) Performing a water mouthwash prior to dosing with
GT-001. The mouthwash can be a rinse with 20 ml of water.
[0153] (13) Giving one milliliter (1 ml) of placebo (formulation
without GT-001) to the participant to the tongue via pipette 5
minutes before lunch.
[0154] (14) The solution remained on the tongue for 1 minute
followed by asking participants to swish and then swallow.
[0155] (15) Completing a VAS for like-lines (VAS completed by
subjects).
[0156] (16) Collecting PK blood samples after each of seven doses
at .+-.1 minute at 5, 10, 15, 30, and .+-.5 minutes at 60, 120, and
240 minutes post dose.
[0157] (17) Isolating subjects from other subjects during
lunch.
[0158] (18) Provided a "ad-libitum" lunch (composed of a casserole,
nutrient drink and two (2) cookies) and recording calorie
intake.
[0159] (19) Having subjects complete VAS questionnaire for
sweetness, sourness, bitterness, saltiness, umami, and fat taste 20
minutes after completing the meals.
[0160] (20) Recording VAS for appetite and satiety every 30 minutes
for 2 hours after completing the meal.
[0161] (21) Discharging subjects. Subjects ate "at-libitum" until
the 12-hour fasting period preceding the next study visit.
[0162] (22) During the SU visit, subjects were restricted from
ingesting gum, candy, tobacco, carbonated drinks, and from
performing exercise. During the meal, subjects were not exposed to
food cues (visual, odor, or hearing) and they should eat in
isolation.
[0163] Days 2, 4, 6, 8, 10, 12 and 14 treatment days are the same
as day 1.
[0164] Days 3, 5, 7, 9, 11, and 13: Washout days
[0165] Participants rest at home.
[0166] Study End (Day 15 and Early Termination Visit
[0167] If an enrolled subject completed day 1-14, or discontinued
from the study prior to the planned SU discharge, the following was
completed:
[0168] (1) Recording reason for discontinuation from the study.
[0169] (2) Updating medical and medication history.
[0170] (3) Completing adverse event assessment.
[0171] (4) Measuring vital signs (BP, HR, and body temperature). BP
and HR were measured twice in the sitting position and twice in the
standing position. If BP is high at baseline sitting (>160
systolic), BP was re-checked after participant is sitting for 5-10
minutes. Body temperature was measured once.
[0172] (5) Measuring body weight and BMI.
[0173] (6) Performing physical examination, including inspection of
the lingual mucosa.
[0174] (7) Conducting clinical laboratory tests (serum chemistry,
hematology, and urinalysis).
[0175] (8) Measuring GT-001 serum level with anti-GT-001
antibodies.
[0176] (9) Giving serum pregnancy test.
[0177] (10) Performing urine drug screen, urine cotinine test, and
alcohol breath test.
[0178] (11) Diet: Meals details
[0179] (a) Breakfast: Participants provided with macronutrient
balanced breakfast (approximately 325-400 calories). Participants
selected their type of breakfast between eggs, cereal, toast, etc.
Juices, milk and coffee were permitted within the allotted
calories. No artificial sweeteners were permitted.
[0180] (b) Lunch: Participants provided with all you can eat
casserole, juice/milk, and two (2) cookies. Total food intake and
VAS appetite and satiety was recorded. No artificial sweeteners
were permitted.
[0181] (c) In between meals: Participants can only have water in
between meals. Participants were restricted from gum, candy,
tobacco, and carbonated drinks.
Example 2--VAS Assessment
[0182] The following exemplary VAS Assessment was given to subjects
to assess their feeling of fullness before and after receiving
PYY(3-36) or placebo and before or after eating at various doses
described herein. Participants indicated their response on a scale
of 1-10 with 1 indicating the strongest response on the left and 10
indicating the strongest response on the right. For example, if a
participant indicated a response of 1 for question a, they were not
hungry at all. A response of 10 for question a indicated they have
never been hungrier. A response of 5 indicates they felt in between
"I am not hungry at all" and "I have never been more hungry." The
numerical responses on a scale of 1-10 were tabulated and used to
generate the graphs of FIGS. 1 and 2.
TABLE-US-00022 a I am not hungry at all How hungry do you feel? I
have never been more hungry b I am comptetely empty How satisfied
do you feel? I cannot eat another bite c Not at all full How full
do you feel? Totally full d Nothing at all How much do you think
you can eat? A lot
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