U.S. patent application number 17/829439 was filed with the patent office on 2022-09-15 for treatment of gastroparesis with triazaspiro[4.5]decanone.
The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Emil Chuang.
Application Number | 20220288042 17/829439 |
Document ID | / |
Family ID | 1000006374123 |
Filed Date | 2022-09-15 |
United States Patent
Application |
20220288042 |
Kind Code |
A1 |
Chuang; Emil |
September 15, 2022 |
TREATMENT OF GASTROPARESIS WITH TRIAZASPIRO[4.5]DECANONE
Abstract
Provided herein is a method of treating or alleviating one or
more symptoms of a disorder, disease, or condition mediated by a
dopamine D.sub.2 or D.sub.3 receptor with
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof. Also provided herein is a method of increasing the scrum
prolactin level with
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5-
]decan-3-yl)methyl)benzoic acid or a pharmaceutically acceptable
salt thereof.
Inventors: |
Chuang; Emil; (Cambridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Family ID: |
1000006374123 |
Appl. No.: |
17/829439 |
Filed: |
June 1, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17526401 |
Nov 15, 2021 |
|
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17829439 |
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16610863 |
Nov 4, 2019 |
11202776 |
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PCT/US2018/032270 |
May 11, 2018 |
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17526401 |
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62547686 |
Aug 18, 2017 |
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62505662 |
May 12, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/14 20180101; A61K
31/438 20130101 |
International
Class: |
A61K 31/438 20060101
A61K031/438; A61P 1/14 20060101 A61P001/14 |
Claims
1. A method of treating or alleviating one or more symptoms of
gastroparesis in a subject, comprising administering to the subject
a therapeutically effective amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
2. A method of treating or alleviating one or more symptoms of a
disorder, disease, or condition characterized by delayed gastric
emptying in a subject, comprising administering to the subject a
therapeutically effective amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
3. The method of claim 2, wherein the disorder, disease, or
condition is gastroparesis.
4. The method of claim 1 or 3, wherein the gastroparesis is
diabetic or idiopathic gastroparesis.
5. The method of any one of claims 1 to 4, wherein the one or more
symptoms are abdominal pain, belching, bloating, early satiety,
epigastric pain or discomfort, excess gas, heartburn, loss of
appetite, nausea, postprandial fullness, regurgitation, swollen
abdomen, vomiting, or a combination thereof.
6. The method of any one of claims 1 to 5, wherein the one or more
symptoms are abdominal pain, bloating, early satiety, epigastric
pain or discomfort, nausea, postprandial fullness, vomiting, or a
combination thereof.
7. The method of any one of claims 1 to 6, wherein the one or more
symptoms are belching, bloating, heartburn, indigestion, nausea,
regurgitation, vomiting, or a combination thereof.
8. A method of increasing the serum prolactin concentration in a
subject, comprising administering to the subject a therapeutically
effective amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspir-
o[4.5]decan-3-yl)methyl)benzoic acid or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate
or hydrate thereof.
9. The method of claim 8, wherein the therapeutically effective
amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is the amount sufficient to increase the
serum prolactin level to a concentration ranging from about 10 to
about 500 ng/mL.
10. The method of claim 8 or 9, wherein the therapeutically
effective amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspir-
o[4.5]decan-3-yl)methyl)benzoic acid is the amount sufficient to
increase the serum prolactin level to a concentration ranging from
about 50 to about 200 ng/mL.
11. The method of any one of claims 1 to 10, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is administered as a pharmaceutically
acceptable salt, or a pharmaceutically acceptable solvate or
hydrate thereof.
12. The method of claim 11, wherein the pharmaceutically acceptable
salt is a pharmaceutically acceptable salt of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid and maleic acid, or a pharmaceutically
acceptable solvate or hydrate thereof.
13. The method of claim 12, wherein the molar ratio of the maleic
acid to
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is about 1.
14. The method of any one of claims 1 to 13, wherein the
therapeutically effective amount is ranging from about 1 to about
250 mg per day as measured in the amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a maleate salt thereof.
15. The method of claim 14, wherein the therapeutically effective
amount is ranging from about 5 to 200 mg per day as measured in the
amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a maleate salt thereof.
16. The method of claim 14, wherein the therapeutically effective
amount is about 10, about 25, about 50, or about 100 mg per day as
measured in the amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a maleate salt thereof.
17. The method of any one of claims 1 to 16, wherein the
therapeutically effective amount is the amount sufficient to
provide an arithmetic mean AUC.sub..infin. of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 1 to about 500
nghr/mL.
18. The method of claim 17, wherein the therapeutically effective
amount is the amount sufficient to provide an arithmetic mean
AUC.sub..infin. of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 10 to about 200
nghr/mL.
19. The method of any one of claims 1 to 18, wherein the
therapeutically effective amount is the amount sufficient to
provide an arithmetic mean peak plasma concentration (C.sub.max) of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 1 to about 500
ng/mL.
20. The method of claim 19, wherein the therapeutically effective
amount is the amount sufficient to provide an arithmetic mean peak
plasma concentration (C.sub.max) of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 5 to about 50
ng/mL.
21. The method of any one of claims 1 to 20, wherein the
therapeutically effective amount is the amount sufficient to
provide an average steady-state plasma concentration of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 1 to about 500
ng/mL.
22. The method of claim 21, wherein the therapeutically effective
amount is the amount sufficient to provide an average steady-state
plasma concentration of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 5 to about 100
ng/mL.
23. The method of any one of claims 1 to 22, wherein the
therapeutically effective amount is the amount sufficient to
provide an average trough plasma concentration of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 0.01 to about 50
ng/mL.
24. The method of claim 23, wherein the therapeutically effective
amount is the amount sufficient to provide an average trough plasma
concentration of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid ranging from about 0.2 to about 10
ng/mL.
25. The method of any one of claims 1 to 24, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is administered orally or
parenterally.
26. The method of any one of claims 1 to 25, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is administered under fasted
conditions.
27. The method of any one of claims 1 to 26, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid is administered without a food.
28. The method of any one of claims 1 to 27, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-tri
azaspiro[4.5]decan-3-yl)methyl)benzoic acid is administered at
least 30 minutes before a meal.
29. The method of any one of claims 1 to 25, wherein
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-tri
azaspiro[4.5]decan-3-yl)methyl)benzoic acid is administered at
least 1 hour after a meal.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/505,662, filed May 12, 2017, and U.S.
Provisional Application No. 62/547,686, filed Dec. 21, 2017, the
disclosure of each of which is incorporated herein by reference in
its entirety.
FIELD
[0002] Provided herein is a method of treating or alleviating one
or more symptoms of a disorder, disease, or condition mediated by a
dopamine D.sub.2 or D.sub.3 receptor with
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof. Also provided herein is a method of increasing the serum
prolactin level in a subject with
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof.
BACKGROUND
[0003] Gastroparesis is a disorder of the stomach characterized by
delayed gastric emptying in the absence of mechanical obstruction.
Symptoms, including nausea, vomiting, early satiety, abdominal
pain, and postprandial fullness, are chronic with episodic symptom
exacerbation. Parkman et al., Gastroenterology 2004, 127,
1592-1622. The prevalence of gastroparesis in the United States is
24.2 per 100,000. Camilleri et al., Am. J. Gastroenterol. 2013,
108, 18-37. In cases of chronic gastroparesis, diabetic (29%),
postsurgical (13%), and idiopathic (36%) etiologies comprise the
majority of cases in the tertiary referral setting. Hyett et al.,
Gastroenterology 2009, 137, 445-452. Gastroparesis can result in
nutritional compromise, impaired glucose control, and a poorer
quality of life, independent of other factors such as age, tobacco
and alcohol use, or types of diabetes. Choung et al., Am. J.
Gastroenterol. 2012, 107, 82-88. The impact of gastroparesis as a
serious outcome on day-to-day functioning is well-document both in
terms of patients' deteriorating quality of life, and the direct or
indirect economic burdens placed on society. Parkman et al,
Neurogastroenterol. Motil. 2010, 22, 113-133.
[0004] Currently in the United States, there are no approved
therapies for the chronic treatment of diabetic or idiopathic
gastroparesis. Metoclopramide is a FDA-approved medication for the
short term treatment of acute and recurrent diabetic gastroparesis.
Lee and Kuo, Expert. Rev. Endocrinol. Metab. 2010, 5, 653-662.
However, its dosage and duration of treatment are limited by its
well-documented toxicities, the most notable of which is a category
of movement disorders known as extrapyramidal symptoms (EPS). Id.;
Meltzer, Ann. Rev. Med. 2013, 64, 393-406. Of greatest concern is
tardive dyskinesia, a severe and often irreversible EPS. The risk
of developing tardive dyskinesia increases with dose level and
duration of treatment. Lee and Kuo, Expert. Rev. Endocrinol. Metab.
2010, 5, 653-662. Thus, the package insert of metoclopramide in the
United States includes a black box warning regarding its chronic
use for longer than 12 weeks. Id. Domperidone is marketed for use
as an anti-emetic and prokinetic agent in a number of countries
worldwide, although not in the United States due to its
cardiovascular safety profile, which includes a risk for
drug-induced long QT syndrome, torsades de pointes, and sudden
cardiac death. Michaud and Turgeon, Cardiovasc. Pharmacol. 2013,
61, 215-217. Owing to safety concerns, both metoclopramide and
domperidone are restricted to short term use of less than a week.
See, e.g., Metoclopramide 10 mg Tablets: Summary of Product
Characteristics; Barnstable, North Devon, UK: Actavis UK Ltd.,
Revised 19 Oct. 2016; and Domperidone 10 mg Film-Coated Tablets:
Summary of Product Characteristics; Wrexham, UK: Wockhardt UK Ltd.,
Revised 14 Jun. 2016. Therefore, there is a need for an effective
therapy for gastroparesis.
SUMMARY OF THE DISCLOSURE
[0005] Provided herein is a method of treating or alleviating one
or more symptoms of a disorder, disease, or condition mediated by a
dopamine D.sub.2 or D.sub.3 receptor in a subject, comprising
administering to the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[-
4.5]decan-3-yl)methyl)benzoic acid or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0006] Also provided herein is a method of treating or alleviating
one or more symptoms of gastroparesis in a subject, comprising
administering to the subject
34(1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-
-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0007] Furthermore, provided herein is a method of treating or
alleviating one or more symptoms of a disorder, disease, or
condition characterized by delayed gastric emptying in a subject,
comprising administering to the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[-
4.5]decan-3-yl)methyl)benzoic acid or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0008] Provided herein is a method of enhancing gastrointestinal
motility in a subject, comprising administering to the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0009] Provided herein is a method of increasing the serum
prolactin level in a subject, comprising administering to the
subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows mean plasma concentration-time profiles of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid in fasting subjects following a single
PO dose.
[0011] FIG. 2 shows mean plasma concentration-time profiles of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid in fasting and fed subjects following a
single PO dose.
[0012] FIG. 3 shows mean plasma concentration-time profiles of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid in fasting subjects following multiple
PO doses.
[0013] FIG. 4 shows mean serum prolactin concentration versus
nominal time in fasting subjects following a single PO dose of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid maleate.
[0014] FIG. 5 shows mean serum prolactin concentration versus
nominal time in fasting subjects following multiple PO doses of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid maleate.
DETAILED DESCRIPTION
[0015] To facilitate understanding of the disclosure set forth
herein, a number of terms are defined below.
[0016] Generally, the nomenclature used herein and the laboratory
procedures in organic chemistry, medicinal chemistry, biochemistry,
biology, and pharmacology described herein are those well known and
commonly employed in the art. Unless defined otherwise, all
technical and scientific terms used herein generally have the same
meaning as commonly understood by one of ordinary skill in the art
to which this disclosure belongs.
[0017] The term "subject" refers to an animal, including, but not
limited to, a primate (e.g., human), cow, pig, sheep, goat, horse,
dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient"
are used interchangeably herein in reference, for example, to a
mammalian subject, such as a human subject. In one embodiment, the
subject is a human.
[0018] The terms "treat," "treating," and "treatment" are meant to
include alleviating or abrogating a disorder, disease, or
condition, or one or more of the symptoms associated with the
disorder, disease, or condition; or alleviating or eradicating the
cause(s) of the disorder, disease, or condition itself.
[0019] The terms "alleviate" and "alleviating" refer to easing or
reducing one or more symptoms (e.g., pain) of a disorder, disease,
or condition. The terms can also refer to reducing adverse effects
associated with an active ingredient. Sometimes, the beneficial
effects that a subject derives from a prophylactic or therapeutic
agent do not result in a cure of the disorder, disease, or
condition.
[0020] The term "therapeutically effective amount" or "effective
amount" is meant to include the amount of a compound that, when
administered, is sufficient to prevent development of, or alleviate
to some extent, one or more of the symptoms of the disorder,
disease, or condition being treated. The term "therapeutically
effective amount" also refers to the amount of a compound that is
sufficient to elicit a biological or medical response of a
biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,
tissue, system, animal, or human, which is being sought by a
researcher, veterinarian, medical doctor, or clinician.
[0021] The term "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable excipient," "physiologically
acceptable carrier," or "physiologically acceptable excipient"
refers to a pharmaceutically acceptable material, composition, or
vehicle, such as a liquid or solid filler, diluent, solvent, or
encapsulating material. In one embodiment, each component is
"pharmaceutically acceptable" in the sense of being compatible with
the other ingredients of a pharmaceutical formulation, and suitable
for use in contact with the tissue or organ of a subject (e.g., a
human or an animal) without excessive toxicity, irritation,
allergic response, immunogenicity, or other problems or
complications, commensurate with a reasonable benefit/risk ratio.
See, Remington: The Science and Practice of Pharmacy, 22nd ed.;
Allen Ed.: Philadelphia, Pa., 2012; Handbook of Pharmaceutical
Excipients, 7th ed.; Rowe et al., Eds.; The Pharmaceutical Press
and the American Pharmaceutical Association: 2012; Handbook of
Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower
Publishing Company: 2007; Pharmaceutical Preformulation and
Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla.,
2009.
[0022] The term "about" or "approximately" means an acceptable
error for a particular value as determined by one of ordinary skill
in the art, which depends in part on how the value is measured or
determined. In certain embodiments, the term "about" or
"approximately" means within 1, 2, 3, or 4 standard deviations. In
certain embodiments, the term "about" or "approximately" means
within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,
0.5%, or 0.05% of a given value or range.
[0023] The term "solvate" refers to a complex or aggregate formed
by one or more molecules of a solute, e.g., a compound described
herein, and one or more molecules of a solvent, which present in
stoichiometric or non-stoichiometric amount. Suitable solvents
include, but are not limited to, water, methanol, ethanol,
n-propanol, isopropanol, and acetic acid. In certain embodiments,
the solvent is pharmaceutically acceptable. In one embodiment, the
complex or aggregate is in a crystalline form. In another
embodiment, the complex or aggregate is in a noncrystalline form.
Where the solvent is water, the solvate is a hydrate. Examples of
hydrates include, but are not limited to, a hemihydrate,
monohydrate, dihydrate, trihydrate, tetrahydrate, and
pentahydrate.
Methods of Use
[0024] In one embodiment, provided herein is a method of treating
or alleviating one or more symptoms of a disorder, disease, or
condition mediated by a dopamine D.sub.2 or D.sub.3 receptor in a
subject, comprising administering to the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid (hereinafter, "Compound 1") or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate or hydrate thereof.
[0025] In another embodiment, provided herein is a method of
treating or alleviating one or more symptoms of a disorder,
disease, or condition mediated by a dopamine D.sub.2 or D.sub.3
receptor in a subject, comprising administering to the subject a
therapeutically effective amount of Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate or hydrate thereof.
[0026] In certain embodiments, the disorder, disease, or condition
is mediated by a dopamine D.sub.2 receptor. In certain embodiments,
the disorder, disease, or condition is mediated by a dopamine
D.sub.3 receptor. In certain embodiments, the disorder, disease, or
condition is mediated by dopamine D.sub.2 and D.sub.3
receptors.
[0027] In certain embodiments, the disorder, disease, or condition
mediated by a dopamine D.sub.2 or D.sub.3 receptor is a
gastrointestinal disease. In certain embodiments, the disorder,
disease, or condition mediated by a dopamine D.sub.2 or D.sub.3
receptor is constipation, dyspepsia, functional dyspepsia,
gastroesophageal reflux disease (GERD), gastroparesis (also known
as gastric stasis), heartburn, irritable bowel syndrome (IBS),
opioid-induced ileus, postoperative ileus, postprandial distress
syndrome, or visceral hypersensitivity. In certain embodiments, the
disorder, disease, or condition mediated by a dopamine D.sub.2 or
D.sub.3 receptor is chronic unexplained nausea and vomiting, cyclic
vomiting syndrome, drug induced nausea, or postoperative nausea and
vomiting. In certain embodiments, the disorder, disease, or
condition mediated by a dopamine D.sub.2 or D.sub.3 receptor is a
gastrointestinal motility disorder. In certain embodiments, the
disorder, disease, or condition mediated by a dopamine D.sub.2 or
D.sub.3 receptor is gastroparesis. In certain embodiments, the
disorder, disease, or condition mediated by a dopamine D.sub.2 or
D.sub.3 receptor is diabetic gastroparesis. In certain embodiments,
the disorder, disease, or condition mediated by a dopamine D.sub.2
or D.sub.3 receptor is symptomatic diabetic gastroparesis. In
certain embodiments, the disorder, disease, or condition mediated
by a dopamine D.sub.2 or D.sub.3 receptor is idiopathic
gastroparesis. In certain embodiments, the disorder, disease, or
condition mediated by a dopamine D.sub.2 or D.sub.3 receptor is
symptomatic idiopathic gastroparesis. In certain embodiments, the
disorder, disease, or condition mediated by a dopamine D.sub.2 or
D.sub.3 receptor is gastroparesis associated with Parkinson
disease, cancer, a viral infection, or a connective tissue disease.
In certain embodiments, the disorder, disease, or condition
mediated by a dopamine D.sub.2 or D.sub.3 receptor is gastroparesis
associated with a gastric surgery, including, but not limited to,
gastrectomy, gastric bypass, gastric banding, bariatric endoscopy,
pyloroplasty, vagotomy, or fundoplication. In certain embodiments,
the disorder, disease, or condition mediated by a dopamine D.sub.2
or D.sub.3 receptor is gastroparesis associated with a gastric
surgery that manipulates the natural anatomy of the stomach. In
certain embodiments, the disorder, disease, or condition mediated
by a dopamine D.sub.2 or D.sub.3 receptor is gastroparesis
associated with a medication that affects gastric emptying,
including, but not limited to, opioids, glucagon-like peptide-1
analogs (e.g., exenatide and liraglutide), amylin analogs (e.g.,
pramlintide), and cannabinoids.
[0028] In certain embodiments, the symptom of the disorder,
disease, or condition mediated by a dopamine D.sub.2 or D.sub.3
receptor is abdominal pain, belching, bloating, early satiety,
epigastric pain or discomfort, excess gas, heartburn, loss of
appetite, nausea, postprandial fullness, regurgitation, swollen
abdomen, vomiting, or a combination thereof. In certain
embodiments, the symptom of the disorder, disease, or condition
mediated by a dopamine D.sub.2 or D.sub.3 receptor is abdominal
pain, bloating, early satiety, epigastric pain or discomfort,
nausea, postprandial fullness, vomiting, or a combination thereof.
In certain embodiments, the symptom of the disorder, disease, or
condition mediated by a dopamine D.sub.2 or D.sub.3 receptor is
belching, bloating, heartburn, indigestion, nausea, regurgitation,
vomiting, or a combination thereof. In certain embodiments, the
symptom of the disorder, disease, or condition mediated by a
dopamine D.sub.2 or D.sub.3 receptor is epigastric pain, diffuse
abdominal pain, or pain associated with bowel movement.
[0029] In one embodiment, provided herein is a method of treating
or alleviating one or more symptoms of a disorder, disease, or
condition characterized by delayed gastric emptying in a subject,
comprising administering to the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0030] In one embodiment, the disorder, disease, or condition
characterized by delayed gastric emptying is a disorder, disease,
or condition mediated by a dopamine D.sub.2 or D.sub.3 receptor. In
another embodiment, the disorder, disease, or condition
characterized by delayed gastric emptying is gastroparesis.
[0031] In one embodiment, provided herein is a method of treating
or alleviating one or more symptoms of gastroparesis in a subject,
comprising administering to the subject: Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate or hydrate thereof.
[0032] In another embodiment, provided herein is a method of
treating or alleviating one or more symptoms of gastroparesis in a
subject, comprising administering to the subject: a therapeutically
effective amount of Compound 1 or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0033] In certain embodiments, the gastroparesis is diabetic
gastroparesis. In certain embodiments, the gastroparesis is
symptomatic diabetic gastroparesis. In certain embodiments, the
gastroparesis is idiopathic gastroparesis. In certain embodiments,
the gastroparesis is symptomatic idiopathic gastroparesis.
[0034] In certain embodiments, the symptom of gastroparesis is
abdominal pain, belching, bloating, early satiety, epigastric pain
or discomfort, excess gas, heartburn, loss of appetite, nausea,
postprandial fullness, regurgitation, swollen abdomen, vomiting, or
a combination thereof. In certain embodiments, the symptom of
gastroparesis is abdominal pain, bloating, early satiety,
epigastric pain or discomfort, nausea, postprandial fullness,
vomiting, or a combination thereof. In certain embodiments, the
symptom of gastroparesis is belching, bloating, heartburn,
indigestion, nausea, regurgitation, vomiting, or a combination
thereof.
[0035] In one embodiment, provided herein is a method of treating
or alleviating gastroparesis accompanied with nausea, vomiting,
early satiety, abdominal pain, postprandial fullness or a
combination thereof in a subject, comprising administering to the
subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0036] In one embodiment, provided herein is a method of enhancing
gastrointestinal motility in a subject, comprising administering to
the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[-
4.5]decan-3-yl)methyl)benzoic acid or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0037] In one embodiment, provided herein is a method of increasing
the serum prolactin level in a subject, comprising administering to
the subject
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[-
4.5]decan-3-yl)methyl)benzoic acid or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0038] In another embodiment, provided herein is a method of
increasing the serum prolactin level in a subject, comprising
administering to the subject a therapeutically effective amount of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate or hydrate
thereof.
[0039] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to increase the serum prolactin level to a
concentration ranging from about 10 to about 500 ng/mL, from about
10 to about 200 ng/mL, from about 20 to about 200 ng/mL, or from
about 50 to about 200 ng/mL.
[0040] Compound 1, i.e.,
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid, has the following structure:
##STR00001##
[0041] In certain embodiments, Compound 1 is prepared according to
the procedures as described in U.S. Pat. No. 8,691,836 or
9,156,940, the disclosure of each of which is incorporated herein
by reference in its entirety.
[0042] In certain embodiments, Compound 1 is administered as a
pharmaceutically acceptable salt, or a pharmaceutically acceptable
solvate or hydrate thereof. In certain embodiments, Compound 1 is
administered as a pharmaceutically acceptable salt with an acid, or
a pharmaceutically acceptable solvate or hydrate thereof. In
certain embodiments, the acid is selected from: acetic acid,
2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic
acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic
acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,
camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric
acid, caproic acid, caprylic acid, cinnamic acid, citric acid,
cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxoglutaric acid,
glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,
hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0043] In certain embodiments, Compound 1 is administered as a
pharmaceutically acceptable salt with a maleic acid (i.e., a
maleate salt), or a pharmaceutically acceptable solvate or hydrate
thereof; in one embodiment, the molar ratio of maleic acid to
Compound 1 is about 1.
[0044] In certain embodiments, Compound 1 is administered as a
pharmaceutically acceptable salt with a base, or a pharmaceutically
acceptable solvate or hydrate thereof. In certain embodiments, the
base is selected from: calcium hydroxide, magnesium hydroxide,
potassium hydroxide, sodium hydroxide, zinc hydroxide, L-argentine,
benethamine, benzathine, choline, decanal, diethanolamine,
diethylamine, dimethylamine, dipropylamine, diisopropylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylamine,
ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,
1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,
methylamine, piperidine, piperazine, propylamine, pyrrolidine,
1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,
isoquinoline, triethanolamine, trimethylamine, triethylamine,
N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,
and tromethamine.
[0045] In certain embodiments, Compound 1 is administered at a
dosage ranging from about 1 to about 500, from about 2 to about
300, from about 5 to about 200, or from about 5 to about 100 mg per
day as measured in the amount of free Compound 1 or a maleate salt
thereof. In certain embodiments, Compound 1 is administered at a
dosage of about 5, about 10, about 25, about 50, about 100, about
200, or about 300 mg per day as measured in the amount of free
Compound 1 or a maleate salt thereof. In certain embodiments,
Compound 1 is administered at a dosage of about 5, about 10, about
15, about 20, about 25, about 30, about 35, about 40, about 45,
about 50, about 60, about 70, about 80, about 90, about 100, about
110, about 120, about 130, about 140, or about 150 mg per day as
measured in the amount of free Compound 1 or a maleate salt
thereof. In certain embodiments, Compound 1 is administered at a
dosage of about 5, about 10, about 25, about 50, about 100, about
200, or about 300 mg per day as measured in the amount of free
Compound 1 or a maleate salt thereof. In certain embodiments,
Compound 1 is administered at a dosage of about 10, about 25, about
50, or about 200 mg per day as measured in the amount of free
Compound 1 or a maleate salt thereof. In certain embodiments,
Compound 1 is administered at a dosage of about 5, about 25, or
about 50 mg twice daily as measured in the amount of free Compound
1 or a maleate salt thereof. In certain embodiments, Compound 1 is
administered at a dosage of about 5 mg twice daily as measured in
the amount of free Compound 1 or a maleate salt thereof up to 12
weeks. In certain embodiments, Compound 1 is administered at a
dosage of about 25 mg twice daily as measured in the amount of free
Compound 1 or a maleate salt thereof up to 12 weeks. In certain
embodiments, Compound 1 is administered at a dosage of about 50 mg
twice daily as measured in the amount of free Compound 1 or a
maleate salt thereof up to 12 weeks.
[0046] In certain embodiments, Compound 1 is administered at a
dosage ranging from about 1 to about 250, from about 1 to about
200, from about 1 to about 100, or from about 2 to about 50 mg per
day as measured in the amount of free Compound 1 or a maleate salt
thereof. In certain embodiments, Compound 1 is administered at a
dosage of about 1, about 2, about 5, about 10, about 15, about 20,
about 25, about 30, about 35, about 40, about 45, about 50 mg per
day as measured in the amount of free Compound 1 or a maleate salt
thereof. In certain embodiments, Compound 1 is administered at a
dosage of about 10, about 25, or about 50 mg per day as measured in
the amount of free Compound 1 or a maleate salt thereof.
[0047] In certain embodiments, the therapeutically effective amount
of Compound 1 is ranging from about 1 to about 500, from about 2 to
about 300, from about 5 to about 200, or from about 5 to about 100
mg per day as measured in the amount of free Compound 1 or a
maleate salt thereof. In certain embodiments, the therapeutically
effective amount of Compound 1 is about 5, about 10, about 25,
about 50, about 100, about 200, or about 300 mg per day as measured
in the amount of free Compound 1 or a maleate salt thereof. In
certain embodiments, the therapeutically effective amount of
Compound 1 is about 5, about 10, about 15, about 20, about 25,
about 30, about 35, about 40, about 45, about 50, about 60, about
70, about 80, about 90, about 100, about 110, about 120, about 130,
about 140, or about 150 mg per day as measured in the amount of
free Compound 1 or a maleate salt thereof. In certain embodiments,
the therapeutically effective amount of Compound 1 is about 5,
about 10, about 25, about 50, about 100, about 200, or about 300 mg
per day as measured in the amount of free Compound 1 or a maleate
salt thereof. In certain embodiments, the therapeutically effective
amount of Compound 1 is about 10, about 25, about 50, or about 200
mg per day as measured in the amount of free Compound 1 or a
maleate salt thereof.
[0048] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to provide an arithmetic mean area under the
curve (AUC) of Compound 1 in the range from about 1 to about 500
nghr/mL, from about 2 to 500 nghr/mL, from about 5 to 500 nghr/mL,
from about 5 to 200 nghr/mL, from about 5 to 100 nghr/mL, from
about 5 to 50 nghr/mL, or from about 10 to 50 nghr/mL. In certain
embodiments, Compound 1, or a pharmaceutical acceptable solvate or
hydrate thereof, is administered in a sufficient amount to provide
an arithmetic mean AUC of Compound 1 in the range from about 10 to
about 200 nghr/mL.
[0049] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to provide an arithmetic mean AUC.sub..infin. of
Compound 1 in the range from about 1 to about 500 nghr/mL, from
about 2 to 500 nghr/mL, from about 5 to 500 nghr/mL, from about 5
to 200 nghr/mL, from about 5 to 100 nghr/mL, from about 5 to 50
nghr/mL, or from about 10 to 50 nghr/mL. In certain embodiments,
Compound 1, or a pharmaceutical acceptable solvate or hydrate
thereof, is administered in a sufficient amount to provide an
arithmetic mean AUC.sub..infin. of Compound 1 in the range from
about 10 to about 200 ng hr/mL.
[0050] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to provide an arithmetic mean peak plasma
concentration (C.sub.max) of Compound 1 ranging from about 1 to
about 500 ng/mL, from about 1 to about 200 ng/mL, from about 1 to
about 100 ng/mL, from about 1 to about 50 ng/mL, from about 2 to
about 50 ng/mL from about 5 to about 50 ng/mL, or from about 5 to
about 20 ng/mL. In certain embodiments, Compound 1, or a
pharmaceutical acceptable solvate or hydrate thereof, is
administered in a sufficient amount to provide an arithmetic mean
C.sub.max of Compound 1 ranging from about 5 to about 50 ng/mL,
[0051] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to provide an average steady-state plasma
concentration of Compound 1 ranging from about 1 to about 500
ng/mL, from about 1 to about 200 ng/mL, from about 1 to about 100
ng/mL, from about 1 to about 50 ng/mL, from about 2 to about 50
ng/mL from about 2 to about 50 ng/mL, from about 2 to about 20
ng/mL, or from about 5 to about 20 ng/mL. In certain embodiments,
Compound 1, or a pharmaceutical acceptable solvate or hydrate
thereof, is administered in a sufficient amount to provide an
average steady-state plasma concentration of Compound 1 ranging
from about 5 to about 100 ng/mL.
[0052] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered in a
sufficient amount to provide an average trough plasma concentration
or average minimum concentration of Compound 1 ranging from about
0.01 to about 10 ng/mL, from about 0.05 to about 5 ng/mL, from
about 0.1 to about 2 ng/mL, or from about 0.2 to about 1 ng/mL. In
certain embodiments, Compound 1, or a pharmaceutical acceptable
solvate or hydrate thereof, is administered in a sufficient amount
to provide an average trough plasma concentration or average
minimum concentration of Compound 1 ranging from about 0.2 to about
10 ng/mL.
[0053] In certain embodiments, the subject is a mammal. In certain
embodiments, the subject is a human.
[0054] The methods provided herein encompass treating a subject
regardless of patient's age, although some diseases or disorders
are more common in certain age groups.
[0055] Depending on the disease to be treated and the subject's
conditions, Compound 1 or a pharmaceutically acceptable salt
thereof, or a pharmaceutical acceptable solvate or hydrate thereof,
may be administered by an oral, parenteral (e.g., intramuscular,
intraperitoneal, intravenous, CIV, intracistemal injection or
infusion, subcutaneous injection, or implant), inhalation, nasal,
vaginal, rectal, sublingual, or topical (e.g., transdermal or
local) route of administration.
[0056] Compound 1 or a pharmaceutically acceptable salt thereof, or
a pharmaceutical acceptable solvate or hydrate thereof, may be
formulated, alone or together, in a suitable dosage unit with
pharmaceutically acceptable excipients, carriers, adjuvants and
vehicles, appropriate for each route of administration. In one
embodiment, Compound 1 or a pharmaceutically acceptable salt
thereof, or a pharmaceutical acceptable solvate or hydrate thereof,
is administered orally. In another embodiment, Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered
parenterally. In yet another embodiment, Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered
intravenously. In yet another embodiment, Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered
intramuscularly. In yet another embodiment, Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered
subcutaneously. In still another embodiment, Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered
topically.
[0057] Compound 1 or a pharmaceutically acceptable salt thereof, or
a pharmaceutical acceptable solvate or hydrate thereof, can also be
formulated as modified release dosage forms, including delayed-,
extended-, prolonged-, sustained-, pulsatile-, controlled-,
accelerated-, fast-, targeted-, programmed-release, and gastric
retention dosage forms. These dosage forms can be prepared
according to conventional methods and techniques known to those
skilled in the art (see, Remington: The Science and Practice of
Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd
Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York,
N.Y., 2008).
[0058] In one embodiment, Compound 1 is formulated in a dosage form
for oral administration, which comprises Compound 1 or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
acceptable solvate or hydrate thereof, and a pharmaceutically
acceptable excipient.
[0059] The oral dosage can be provided in a solid, semisolid, or
liquid dosage form. As used herein, oral administration also
includes buccal, lingual, and sublingual administration. Suitable
oral dosage forms include, but are not limited to, tablets,
fastmelts, chewable tablets, capsules, pills, strips, troches,
lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk
powders, effervescent or non-effervescent powders or granules, oral
mists, solutions, emulsions, suspensions, wafers, sprinkles,
elixirs, and syrups. In addition to the active ingredient(s), e.g.,
Compound 1 or a pharmaceutically acceptable salt thereof, or a
pharmaceutical acceptable solvate or hydrate thereof, the oral
dosage form can contain one or more pharmaceutically acceptable
excipients, including, but not limited to, binders, fillers,
diluents, disintegrants, wetting agents, lubricants, glidants,
coloring agents, dye-migration inhibitors, sweetening agents,
flavoring agents, emulsifying agents, suspending and dispersing
agents, preservatives, solvents, non-aqueous liquids, organic
acids, and sources of carbon dioxide.
[0060] Suitable binders or granulators include, but are not limited
to, starches, such as corn starch, potato starch, and
pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such
as sucrose, glucose, dextrose, molasses, and lactose; natural and
synthetic gums, such as acacia, alginic acid, alginates, extract of
Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks,
carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone
(PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar
gum; celluloses, such as ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose,
methyl cellulose, hydroxyethylcellulose (HEC),
hydroxypropylcellulose (HPC), and hydroxypropyl methyl cellulose
(HPMC); microcrystalline celluloses, such as AVICEL-PH-101,
AVICEL-PH-102, AVICEL-PH-103, AVICEL RC-581, and AVICEL-PH-105 (FMC
Corp., Marcus Hook, Pa.); and mixtures thereof.
[0061] Suitable diluents include, but are not limited to, dicalcium
phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol,
cellulose, kaolin, mannitol, sodium chloride, dry starch, and
powdered sugar. Certain diluents, such as mannitol, lactose,
sorbitol, sucrose, and inositol, when present in sufficient
quantity, can impart properties to some compressed tablets that
permit disintegration in the mouth by chewing. Such compressed
tablets can be used as chewable tablets.
[0062] Suitable disintegrants include, but are not limited to,
agar; bentonite; celluloses, such as methylcellulose and
carboxymethylcellulose; wood products; natural sponge;
cation-exchange resins; alginic acid; gums, such as guar gum and
Veegum HV; citrus pulp; cross-linked celluloses, such as
croscarmellose; cross-linked polymers, such as crospovidone;
cross-linked starches; calcium carbonate; microcrystalline
cellulose, such as sodium starch glycolate; polacrilin potassium;
starches, such as corn starch, potato starch, tapioca starch, and
pre-gelatinized starch; clays; aligns; and mixtures thereof.
[0063] Suitable lubricants include, but are not limited to, calcium
stearate; magnesium stearate; mineral oil; light mineral oil;
glycerin; sorbitol; mannitol; glycols, such as glycerol behenate
and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate;
talc; hydrogenated vegetable oil, such as peanut oil, cottonseed
oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean
oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch;
lycopodium; silica or silica gels, such as AEROSIL.RTM. 200 (W.R.
Grace Co., Baltimore, Md.) and CAB-O-SIL.RTM. (Cabot Co. of Boston,
Mass.); and mixtures thereof.
[0064] Suitable glidants include, but are not limited to, colloidal
silicon dioxide, CAB-O-SIL.RTM. (Cabot Co. of Boston, Mass.), and
asbestos-free talc.
[0065] Suitable coloring agents include, but are not limited to,
any of the approved, certified, water soluble FD&C dyes, and
water insoluble FD&C dyes suspended on alumina hydrate, and
color lakes and mixtures thereof. A color lake is the combination
by adsorption of a water-soluble dye to a hydrous oxide of a heavy
metal, resulting in an insoluble form of the dye.
[0066] Suitable flavoring agents include, but are not limited to,
natural flavors extracted from plants, such as fruits, and
synthetic blends of compounds, which produce a pleasant taste
sensation, such as peppermint and methyl salicylate.
[0067] Suitable sweetening agents include, but are not limited to,
sucrose, lactose, mannitol, syrups, glycerin, and artificial
sweeteners, such as saccharin and aspartame.
[0068] Suitable emulsifying agents include, but are not limited to,
gelatin, acacia, tragacanth, bentonite, and surfactants, such as
polyoxyethylene sorbitan monooleate (TWEEN.RTM. 20),
polyoxyethylene sorbitan monooleate 80 (TWEEN.RTM. 80), and
triethanolamine oleate.
[0069] Suitable suspending and dispersing agents include, but are
not limited to, sodium carboxymethylcellulose, pectin, tragacanth,
Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl
methylcellulose, and polyvinylpyrrolidone.
[0070] Suitable preservatives include, but are not limited to,
glycerin, methyl and propylparaben, benzoic add, sodium benzoate
and alcohol.
[0071] Suitable wetting agents include, but are not limited to,
propylene glycol monostearate, sorbitan monooleate, diethylene
glycol monolaurate, and polyoxyethylene lauryl ether.
[0072] Suitable solvents include, but are not limited to, glycerin,
sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids
utilized in emulsions include, but are not limited to, mineral oil
and cottonseed oil.
[0073] Suitable organic acids include, but are not limited to,
citric and tartaric acid. Suitable sources of carbon dioxide
include, but are not limited to, sodium bicarbonate and sodium
carbonate.
[0074] It should be understood that many carriers and excipients
may serve several functions, even within the same formulation.
[0075] The oral dosage form can be provided as compressed tablets,
tablet triturates, chewable lozenges, rapidly dissolving tablets,
multiple compressed tablets, or enteric-coating tablets,
sugar-coated, or film-coated tablets. Enteric-coated tablets are
compressed tablets coated with substances that resist the action of
stomach acid but dissolve or disintegrate in the intestine, thus
protecting the active ingredients from the acidic environment of
the stomach. Enteric-coatings include, but are not limited to,
fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated
shellac, and cellulose acetate phthalates. Sugar-coated tablets are
compressed tablets surrounded by a sugar coating, which may be
beneficial in covering up objectionable tastes or odors and in
protecting the tablets from oxidation. Film-coated tablets are
compressed tablets that are covered with a thin layer or film of a
water-soluble material. Film coatings include, but are not limited
to, hydroxyethylcellulose, sodium carboxymethylcellulose,
polyethylene glycol 4000, and cellulose acetate phthalate. Film
coating imparts the same general characteristics as sugar coating.
Multiple compressed tablets are compressed tablets made by more
than one compression cycle, including layered tablets, and
press-coated or dry-coated tablets.
[0076] The oral dosage form can be provided as soft or hard
capsules, which can be made from gelatin, methylcellulose, starch,
or calcium alginate. The hard gelatin capsule, also known as the
dry-filled capsule (DFC), consists of two sections, one slipping
over the other, thus completely enclosing the active ingredient.
The soft elastic capsule (SEC) is a soft, globular shell, such as a
gelatin shell, which is plasticized by the addition of glycerin,
sorbitol, or a similar polyol. The soft gelatin shells may contain
a preservative to prevent the growth of microorganisms. Suitable
preservatives are those as described herein, including methyl- and
propyl-parabens, and sorbic acid. The liquid, semisolid, and solid
dosage forms provided herein may be encapsulated in a capsule.
Suitable liquid and semisolid dosage forms include solutions and
suspensions in propylene carbonate, vegetable oils, or
triglycerides. Capsules containing such solutions can be prepared
as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
The capsules may also be coated as known by those of skill in the
art in order to modify or sustain dissolution of the active
ingredient.
[0077] The oral dosage form can be provided in liquid and semisolid
dosage forms, including emulsions, solutions, suspensions, elixirs,
and syrups. An emulsion is a two-phase system, in which one liquid
is dispersed in the form of small globules throughout another
liquid, which can be oil-in-water or water-in-oil. Emulsions may
include a pharmaceutically acceptable non-aqueous liquid or
solvent, emulsifying agent, and preservative. Suspensions may
include a pharmaceutically acceptable suspending agent and
preservative. Aqueous alcoholic solutions may include a
pharmaceutically acceptable acetal, such as a di(lower alkyl)
acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl
acetal; and a water-miscible solvent having one or more hydroxyl
groups, such as propylene glycol and ethanol. Elixirs are clear,
sweetened, and hydroalcoholic solutions. Syrups are concentrated
aqueous solutions of a sugar, for example, sucrose, and may also
contain a preservative. For a liquid dosage form, for example, a
solution in a polyethylene glycol may be diluted with a sufficient
quantity of a pharmaceutically acceptable liquid carrier, e.g.,
water, to be measured conveniently for administration.
[0078] The oral dosage form can be formulated as immediate or
modified release dosage forms, including delayed-, sustained,
pulsed-, controlled, targeted-, and programmed-release forms.
[0079] In one embodiment, Compound 1 is formulated in an oral
dosage form, which comprises Compound 1 or a pharmaceutically
acceptable salt thereof, or a pharmaceutical acceptable solvate or
hydrate thereof, and a binder, a disintegrant, and a lubricant.
[0080] In another embodiment, Compound 1 is formulated in an oral
dosage form, which comprises a maleate salt of Compound 1, or a
pharmaceutical acceptable solvate or hydrate thereof, and a binder,
a disintegrant, and a lubricant.
[0081] In yet another embodiment, Compound 1 is provided in an oral
dosage, which comprises a maleate salt of Compound 1, or a
pharmaceutical acceptable solvate or hydrate thereof, and a
microcrystalline cellulose, sodium starch glycolate, and magnesium
stearate.
[0082] In certain embodiments, the oral dosage form is provided as
a tablet or capsule. In certain embodiments, the oral dosage form
is provided as a tablet. In certain embodiments, the oral dosage
form is provided as a capsule.
[0083] Compound 1, or a pharmaceutical acceptable solvate or
hydrate thereof, can be delivered as a single dose such as, e.g., a
single bolus injection, or oral tablets or pills; or over time such
as, e.g., continuous infusion over time or divided bolus doses over
time. Compound 1, or a pharmaceutical acceptable solvate or hydrate
thereof, can be administered repetitively if necessary, for
example, until the patient experiences stable disease or
regression, or until the patient experiences disease progression or
unacceptable toxicity. Stable disease or lack thereof is determined
by methods known in the art, such as evaluation of patient symptoms
and physical examination.
[0084] Compound 1, or a pharmaceutical acceptable solvate or
hydrate thereof, can be administered once daily (QD), or divided
into multiple daily doses such as twice daily (BID), and three
times daily (TID). In addition, the administration can be
continuous, i.e., every day, or intermittently. The term
"intermittent" or "intermittently" as used herein is intended to
mean stopping and starting at either regular or irregular
intervals. For example, intermittent administration of Compound 1,
or a pharmaceutical acceptable solvate or hydrate thereof, is
administration for one to six days per week, administration in
cycles (e.g., daily administration for two to eight consecutive
weeks, then a rest period with no administration for up to one
week), or administration on alternate days.
[0085] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is cyclically administered
to a patient. Cycling therapy involves the administration of an
active agent for a period of time, followed by a rest for a period
of time, and repeating this sequential administration. Cycling
therapy can avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.
[0086] In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered under fasted
conditions. In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered without a
food. In certain embodiments, Compound 1, or a pharmaceutical
acceptable solvate or hydrate thereof, is administered at least 10,
10, or 30 minutes, before a meal. In certain embodiments, Compound
1, or a pharmaceutical acceptable solvate or hydrate thereof, is
administered at least 1, 2, or 3 hours after a meal.
[0087] In certain embodiments, each method provided herein further
independently comprises the step of administering a second
therapeutic agent.
[0088] Compound 1, or a pharmaceutical acceptable solvate or
hydrate thereof, can also be provided as an article of manufacture
using packaging materials well known to those of skill in the art.
See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers, syringes, and any packaging material suitable
for a selected formulation and intended mode of administration and
treatment.
[0089] In certain embodiments, provided herein also are kits which,
when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
subject. In certain embodiments, the kit provided herein includes a
container and a dosage form of Compound 1.
[0090] Kits provided herein can further include devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, needle-less injectors
drip bags, patches, and inhalers. The kits provided herein can also
include condoms for administration of the active ingredients.
[0091] Kits provided herein can further include pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: aqueous vehicles,
including, but not limited to, Water for Injection USP, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles, including, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles, including, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0092] The disclosure will be further understood by the following
non-limiting examples.
EXAMPLES
[0093] As used herein, the symbols and conventions used in these
processes, schemes and examples, regardless of whether a particular
abbreviation is specifically defined, are consistent with those
used in the contemporary scientific literature, for example, the
Journal of the American Chemical Society, the Journal of Medicinal
Chemistry, or the Journal of Biological Chemistry. Specifically,
but without limitation, the following abbreviations may be used in
the examples and throughout the specification: g (grams); mg
(milligrams); mL (milliliters); .mu.L (microliters); mM
(millimolar); .mu.M (micromolar); mmol (millimoles); h (hour or
hours); min (minutes); and HPLC (high pressure liquid
chromatography).
[0094] For all of the following examples, unless otherwise
indicated, all temperatures are expressed in .degree. C. (degrees
Centigrade).
Example 1
Phase I Evaluation of
3-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic Acid Maleate
[0095] A phase I randomized, double-blind, placebo-controlled,
adaptive-design, single-ascending dose (SAD) and multiple-ascending
dose (MAD) study was conducted in healthy human subjects to
evaluate the safety, tolerability, pharmacokinetics (PK),
pharmacodynamics (PD), food effect, and optimal oral dose of
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid maleate (hereinafter, "the Maleate
Salt"). The SAD phase included an arm to evaluate food effect on
the PK of the Maleate Salt. The SAD phase also evaluated the effect
of the Maleate Salt on ECG parameters, including an assessment of
QT-interval changes using exposure-response analysis.
[0096] The Maleate Salt was formulated in the study as
immediate-release, hard gelatin capsules for oral administration.
Each capsule contained 5 mg or 25 mg of the Maleate Salt, as well
as microcrystalline cellulose NF (AVICEL.RTM. PH-102), sodium
starch glycolate NF (EXPLOTAB.RTM.), and magnesium stearate NF, all
filled into a size 3 hard gelatin capsule. A matching placebo
containing the same amount of microcrystalline cellulose NF in
place of the Maleate Salt was used in the study. The Maleate Salt
capsules and matching placebo capsules were packaged in
high-density polyethylene (HDPE) bottles with polypropylene caps
and stored at controlled conditions per the USP.
[0097] A total of 54 subjects received at least 1 dose of the
Maleate Salt, ranging from 5 mg to the maximum single PO dose of
300 mg. Six subjects received a maximum single PO dose of 300 mg
and 5 subjects received a total of 900 mg of the Maleate Salt over
5-day period (100 mg BID for 4 days with single 100 mg on Day
5).
[0098] The SAD phase had 7 cohorts dosed at 5 mg (cohort 1), 10 mg
(cohort 2), 25 mg (cohort 3), 50 mg (cohort 4), 100 mg (cohort 5),
200 mg (cohort 6), and 300 mg (cohort 7) of the Maleate Salt. In
each cohort, there were 6 active- and 2 placebo-treated subjects.
Subjects were administered the Maleate Salt in the fasting state
with 1 exception: subjects in the 25 mg cohort (cohort 3) received
the Maleate Salt while fasting and again after a high-fat breakfast
to determine food effect on PK.
[0099] Mean plasma concentration-time profiles for
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid (hereinafter, "the Compound") following
a single PO dose of the Maleate Salt are shown in FIG. 1. The
concentration-time profiles show rapid absorption and rapid
elimination over 24 h. PK parameters of the Maleate Salt following
single PO doses are summarized in Table 1 below.
[0100] Arithmetic mean C.sub.max ranged from 2.1 ng/mL at the 5 mg
dose level to 191.8 ng/mL at the 300 mg dose level. Median
T.sub.max was about 1.1 h. Arithmetic mean T.sub.1/2 in the fasted
subjects was approximately 1.6 h at the 5 and 10 mg dose levels.
Arithmetic mean T.sub.1/2 in fasted subjects ranged from
approximately 3.1 to 6.0 h at the 25 to 300 mg dose levels.
Arithmetic mean T.sub.1/2 in fasted subjects was approximately 4.0
h across all cohorts in the SAD phase. Exposure to the Maleate Salt
is approximately proportional to the dose administered in the SAD
phase under fasted conditions.
[0101] In evaluating food effect on the PK of the Maleate Salt,
subjects on Day 1 in cohort 3 were administered a single dose of
the Maleate Salt at 25 mg or placebo in the fasted state. On Day 3,
the same subjects received an identical dose 30 minutes after
consumption of a standardized, high-fat, high-calorie breakfast.
Mean plasma concentration-time profiles for the Compound in the
fasted and fed states are shown in FIG. 2. Consumption of the
high-fat meal prior to dosing reduced the extent of absorption
(C.sub.max and AUC), but did not alter T.sub.max (see Table 1
above).
TABLE-US-00001 TABLE 1 Dose Fed T.sub.max C.sub.max AUC.sub.last
AUC.sub..infin. T.sub.1/2 (mg) State (h) (ng/mL) (h ng/mL) (h
ng/mL) (h) 5 Fasted 0.83 2.1 4.3 4.5 1.6 10 Fasted 1.21 6.2 12.9
13.1 1.6 25 Fasted 1.80 10.5 30.5 30.4 6.0 Fed 2.20 6.7 17.6 17.2
7.0 50 Fasted 1.04 22.0 53.2 56.7 3.1 100 Fasted 1.78 48.3 103.8
180.2 5.4 200 Fasted 1.24 105.6 240.1 242.4 5.4 300 Fasted 1.88
191.8 421.3 446.5 5.1
[0102] The MAD phase had 2 cohorts dosed at 50 and 100 mg of the
Maleate Salt. In each cohort, there were 6 active- and 2
placebo-treated subjects. The Maleate Salt was administered to
fasting subjects BID (morning and evening) on Days 1 through 4 and
as a single morning dose on Day 5.
[0103] Mean plasma concentration-time profiles for the Compound in
the MAD phase are shown in FIG. 3. Similar to the SAD phase, plasma
concentration-time profiles in the MAD phase showed rapid
absorption and rapid elimination of the Compound. In addition,
there was little accumulation apparent with the Maleate Salt at 50
or 100 mg BID dosing (less than 40% for C.sub.max and less than 30%
for AUC.sub.12). The mean AI was 1.89 and 1.38 at the 50 and 100 mg
BID dose levels, respectively. PK parameters of the Maleate Salt
for the MAD phase are summarized in Table 2 below.
[0104] On Day 1, mean T.sub.1/2 was approximately 2 h for both 50
and 100 mg BID doses. On Day 5, mean T.sub.1/2 was 11.0 and 6.2 h
following 50 and 100 mg BID doses, respectively. For T.sub.1/2
determination, the plasma samples for Day 1 were only collected to
12 h, whereas the plasma samples for Day 5 were collected to 24 h.
A summary of steady-state PK parameters on Day 5 of the MAD phase
are provided in Table 4 below.
TABLE-US-00002 TABLE 3 Dose Dose T.sub.max C.sub.max T.sub.last
C.sub.last AUC.sub.12 T.sub.1/2 (mg) Day (h) (ng/mL) (h) (ng/mL) (h
ng/mL) (h) 50 1 1.55 23.3 12.0 0.20 53.6 2.0 5 1.17 31.2 24.0 0.18
58.1 11.0 100 1 1.03 71.5 12.0 0.42 152.3 2.1 5 1.53 71.6 24.0 0.28
200.5 6.2
TABLE-US-00003 TABLE 4 Dose T.sub.min C.sub.min C.sub.av, ss (mg)
(h) (ng/mL) (ng/mL) AI 50 8.0 0.32 4.84 1.89 100 4.8 0.65 16.71
1.38
Example 2
Clinical PD Evaluation of
3-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic Acid Maleate
[0105] In the same phase I study, serum prolactin concentrations
were evaluated as a marker of pharmacologic activity (D.sub.2
receptor target engagement). Prolactin is primarily secreted from
lactotroph cells of the anterior pituitary gland, and the release
of prolactin from these cells is under inhibitory control by DA.
Fitzgerald and Dinan, J. Psychopharmacol. 2008, 22, 12-19.
[0106] Concentration-time profiles of serum prolactin for the SAD
and MAD phases are shown in FIGS. 4 and 5, respectively. Following
oral administration of the Maleate Salt, serum prolactin
concentration increased rapidly. The median serum prolactin
T.sub.max was approximately 1.1 h and ranged from 0.7 to 2 h across
all 48 single-dose administration of the Maleate Salt. The
increases were substantial compared to placebo. The prolactin
response was maximal at the 10 mg dose of the Maleate Salt in the
SAD phase. In the MAD phase, there was little if any accumulation
in serum prolactin after BID dosing for 5 days.
Example 3
Evaluation of
3-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic Acid Maleate
[0107] A phase I randomized, double-blind and open-label, placebo
and active-comparator controlled study is conducted to evaluate the
safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics
(PD) of, and food effect on
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid maleate ("the Compound") in subjects
with gastroparesis, in particular, those with diabetes mellitus and
gastroparesis (DG) or with idiopathic gastroparesis (IG). The
effect of the Compound on gastric emptying (GE) is also
determined.
[0108] The study enrolls approximately 48 subjects. The study is
conducted in two parts: Part 1 (double-blind) and Part 2
(open-label). Subjects in Part 1 are randomly assigned (by chance,
like flipping a coin) to one of the four treatment groups, Groups 1
to 4. Subjects in Group 1 each receive 5 mg of the Compound in a
capsule orally, twice daily under fasted conditions for up to 9
days. Subjects in Group 2 each receive 25 mg of the Compound in a
capsule orally, twice daily under fasted conditions for up to 9
days. Subjects in Group 3 each receive 100 mg of the Compound in a
capsule orally, twice daily under fasted conditions for up to 9
days. Subjects in Group 4 each receive a placebo in a matching
capsule orally, twice daily under fasted conditions for up to 9
days. Gastrointestinal emptying is evaluated following a test meal
using a .sup.13C-Spirulina gastric emptying breath test (GEBT), and
GI emptying and motility are evaluated using SmartPill technology.
Blood samples for assessment of the Compound concentrations are
collected at scheduled time points from predose on Day 1 to 48
hours after Day 7 dose. Blood samples for assessment of prolactin
concentrations in serum are collected at screening and scheduled
time points from Day-2 to 48 hours after Day 7 dose. Subject
randomization is stratified by the underlying condition, i.e., DG
versus IG. The assignments remain undisclosed to the subjects and
study doctors during the study (unless there is an urgent medical
need).
[0109] All subjects who complete Part 1 of the study are eligible
for enrollment in Part 2. In Part 2, approximately 6 subjects who
completed Part 1 are enrolled to receive 25 mg of the Compound with
or without food in an open-label crossover design over 2 periods. A
minimum 7-day washout separates the doses in each period. Blood
samples for assessment of the Compound concentrations are collected
from predose to 48 hours after each dose of the Compound.
Furthermore, up to an additional 12 subjects who completed Part 1
of the study are enrolled in the evaluation of the Compound vs
active comparator metoclopramide to confirm the responsiveness of
the GEBT test. Subjects are blinded to treatment until all subjects
have completed Part 1. Blood samples for assessment of the Compound
or metoclopramide concentrations are collected at scheduled time
points from predose on Day 1 to 48 hours postdose.
[0110] The overall time to participate in this study is
approximately 8 weeks. The subjects make a final visit to the
clinic 10-14 days after receiving their last dose of study drug for
a follow-up assessment.
[0111] In both Parts 1 and 2, the subjects are monitored for vital
signs and treatment-emergent adverse events (TEAEs); and by
physical examination, electrocardiograms, and safety laboratory
tests.
[0112] In Part 1, change from baseline in serum prolactin on Day 1
at time of first occurrence of maximum plasma concentration (Tina')
for the Compound is determined. In Part 1, change from baseline in
GEBT (gastric emptying breath test) gastric half-emptying time as
measured by the .sup.13C Spirulina GEBT on Day 1 and 7 is
determined. The GEBT is a nonradioactive, noninvasive, orally
administered test for measuring the rate of solid phase gastric
emptying (GE) in adults. The GEBT measures how fast solid food
moves from the stomach to the small intestine during the digestive
process and aids in the diagnosis of delayed stomach emptying (GP).
GE half-emptying time is the time for half of the ingested solids
to leave the stomach. This value was measured by the .sup.13C
Spirulina GEBT.
[0113] In Part 1, percent change from baseline in GE time as
measured by the SmartPill on Day 7 is determined. SmartPill is an
ingestible capsule that measures pressure, potential of hydrogen
(pH) and temperature as it travels through the gastrointestinal
(GI) tract to assess GI motility. SmartPill eliminates radiation
exposure and is the only motility test that provides a complete
transit profile of the GI tract.
[0114] In Part 1, PK parameters for the Compound, including area
under the plasma concentration-time curve (AUC.sub.T) from 0 to 48
hours over the dosing interval, maximum observed plasma
concentration (C.sub.max), time to reach the maximum plasma
concentration (T.sub.max), terminal disposition phase half-life
(T.sub.1/2Z), and observed plasma concentration at the end of
dosing interval (C.sub.trough) are determined. In Part 2, area
under the plasma concentration-time curve from time 0 to infinity
(AUC.sub..infin.) is determined.
[0115] Eligible subjects for the study are the ones between 18 and
65 years old with a documented diagnosis of DG or IG. Also the
eligible subjects have a body mass index (BMI) greater than or
equal to (>=) 18 and less than or equal to (<=) 35 kilogram
per square meter (kg/m.sup.2) at the screening visit. The eligible
subjects are nonsmokers who have not used tobacco or
nicotine-containing products (example, nicotine patch) for at least
6 months prior to trial drug administration of the initial dose of
trial drug/invasive procedure.
[0116] The eligible subjects have symptoms for GP (that is, chronic
postprandial fullness, abdominal pain, postprandial nausea,
vomiting, loss of appetite and/or early satiety) the past 3 months,
and has documented slow GE, with delayed GE by GEBT at the
screening defined as >=80th percentile. If the eligible subjects
have had a documented scintigraphy or GEBT within the last 12
months that confirms the diagnosis of delayed GE, a screening GEBT
would not be required. The eligible subjects have nausea subscale
(of American Neurogastroenterology and Motility Society
Gastroparesis Cardinal Symptom Index-Daily Diary [ANMS-GCSI-DD])
symptom score >=2 at least 3 of 7 days during the screening. The
eligible subjects have hemoglobin A1c (HBA1c) less than (<) 10
percent (%) (for diabetes mellitus only).
[0117] The subjects who have acute severe gastroenteritis and
pronounced dehydration in the past 48 hours prior to the screening,
gastric pacemaker, chronic parenteral feeding or persistent severe
vomiting are excluded from the study. Also excluded are those who
have a known disturbance of small intestinal absorption, exocrine
pancreatic function, liver metabolism, and pulmonary function; or
who have a history of anorexia nervosa or bulimia, or previous
history of bezoars (the presence of retained liquid, bile, or small
amounts of poorly organized food residue is permitted); or
difficulty swallowing solid food or pills; or prior surgery
involving the luminal GI tract (cholecystectomy, appendectomy, and
hysterectomy are permitted if performed greater than (>) 3
months prior to SmartPill test). The subjects who have any
abdominal or pelvic surgery within the past 3 months; or known or
history of inflammatory bowel disease; or history of
diverticulitis, diverticular stricture, and other intestinal
strictures; or had major surgery, donated or lost 1 unit of blood
(approximately 500 milliliter [mL]) within 4 weeks prior to the
pretrial (screening) visit milligram per deciliter (mg/dL) (14.99
millimole per liter [mmol/L]) during any visit up to and including
the randomization visit (Period 1 Day 1 predose) are also excluded.
The subjects who have had diabetic ketoacidosis (within the prior 4
weeks) are excluded.
Example 4
Phase IIb Evaluation of the Efficacy and Safety of
3-((1-Cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic Acid Maleate in Subjects with Symptomatic
Idiopathic or Diabetic Gastroparesis
[0118] A multicenter, randomized, double-blind, placebo-controlled,
parallel-group, Phase IIb study is conducted to evaluate the
efficacy and safety of twice-daily oral administration of a
peripherally acting dopamine receptor D2/D3 antagonist,
3-((1-cyclohexyl-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]deca-
n-3-yl)methyl)benzoic acid maleate ("the Compound"), for the
treatment of adult subjects with symptomatic idiopathic or diabetic
gastroparesis.
[0119] The study enrolls approximately 280 subjects. Eligible
subjects for the study are adult men and women aged 18 to 85 years,
inclusive, and with body mass index (BMI).gtoreq.19 to .ltoreq.40
kg/m.sup.2 inclusive. The eligible subjects should have experienced
symptoms of gastroparesis (e.g., postprandial fullness, nausea,
vomiting, upper abdominal pain, and early satiety (at least
intermittently)) for at least 3 months before screening as assessed
by a physician. The eligible subjects must have confirmed delayed
gastric emptying at screening; delayed gastric emptying by GEBT is
defined as t.sub.1/2.gtoreq.79 min (80th percentile). The eligible
subjects must have an average composite ANMS GCSI-DD (the American
Neurogastroenterology and Motility Society Gastroparesis Cardinal
Symptom Index-Daily Diary) symptom score .gtoreq.2 during the 7
days before randomization. The predominant symptom experienced by
subjects must not be abdominal pain. The eligible subjects must
experience nausea: nausea subscale (of ANMS GCSI-DD) symptom score
.gtoreq.2 at least 4 of 7 days or an average nausea subscale
symptom .gtoreq.2 during the 7 days before randomization. Nausea
symptoms must not be attributable to a central disorder (e.g.,
motion sickness, glaucoma, menstrual cycles, or migraine headache).
The eligible subjects with diabetes mellitus must have glycosylated
hemoglobin (HbA1c).ltoreq.11% at screening and before
randomization. Given the biological variability of glycemic
parameters, the eligible subjects with a value that does not meet
the above criteria, but is within 0.2% HbA1c of the qualifying
range may, at the discretion of the investigator have a repeat
determination performed at Visit 2 and used as a qualifying
parameter in lieu of the original value.
[0120] Subjects attend a study site for a screening/consent visit
(Visit 1, Day-35), when their consent is obtained and general
eligibility to participate in the study is reviewed. Subjects
discontinue all excluded medication and return to the site up to
approximately 2 weeks later to perform a 4-hour .sup.13C-Spirulina
GEBT (Visit 2). Subjects who are not taking any medications at the
screening visit that require washout may attend the clinic for
Visit 2 earlier than 2 weeks. An 8-hour fast is required before the
GEBT. Subjects have a blood sample taken to check their laboratory
values and then return within 7 days after the GEBT visit to
confirm their eligibility (Visit 3, Day-14). Once eligibility is
confirmed at this visit, eligible subjects are instructed on the
use of an electronic patient reported outcomes (ePRO) tool for
collecting gastroparesis symptom data. The instrument used is the
American Neurogastroenterology and Motility Society Gastroparesis
Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD). The subjects
record their symptoms once daily (in the evening) and return to the
clinic approximately 2 weeks later to assess their gastroparesis
symptom eligibility based on the ANMS GCSI-DD (Visit 4,
Randomization). The subjects need to be compliant with completing
the ANMS GCSI-DD, defined as .gtoreq.80% diary completions, during
the 2-week symptom assessment period.
[0121] The overall time to participate in this study is 17 weeks.
The eligible subjects are randomly assigned to one of four
treatment groups (in 1:1:1:1 ratio), each group stratified by
idiopathic gastroparesis (IG) or diabetic gastroparesis (DG)
(minimum 30 subjects per indication per arm). The assignments
remain undisclosed to the subjects and study doctors during the
study (unless there is an urgent medical need). Subjects in
Treatment Group 1 each receive 5 mg of the Compound in a capsule
orally, twice daily for twelve weeks. Subjects in Treatment Group 2
each receive 25 mg of the Compound in a capsule orally, twice daily
for twelve weeks. Subjects in Treatment Group 3 each receive 50 mg
of the Compound in a capsule orally, twice daily for twelve weeks.
Subjects in Treatment Group 4 each receive a placebo in a matching
capsule orally, twice daily for twelve weeks. All the subjects are
asked to take two capsules at the same time each day throughout the
study. Capsules are taken on an empty stomach (at least 2 hours of
fasting except for water and juice); 1 capsule in the morning
approximately 1 hour before the first meal of the day and another
capsule in the evening approximately 1 hour before the main last
meal of the day, at a regular dose interval. The subjects take
their first study medication at the site on the morning of the
Randomization Visit and take their morning study medication in
clinic at Visits 5, 6, and 7. The subjects complete the ANMS
GCSI-DD daily for 12 weeks and attend the clinic at Weeks 4 (Visit
5), 8 (Visit 6), and 12 (Visit 7) and have additional GEBTs
performed after 4 (Visit 5) and 12 (Visit 7) weeks treatment. At
each visit following randomization, PK samples are taken both
predose and postdose and blood samples for exploratory biomarker
analysis are taken from Visit 2 through Visit 7. A safety follow-up
phone call are made approximately 40 days after last dose of study
medication.
[0122] During the study, four gastroparesis-related symptoms
(nausea, early satiety, postprandial fullness, and upper abdominal
pain) are analyzed by ANMS GCSI-DD. The severity scores of four
gastroparesis-related symptoms (nausea, early satiety, postprandial
fullness, and upper abdominal pain) range from 0 (none) to 4 (very
severe). An ANMS GCSI-DD composite score (nausea, early satiety,
postprandial fullness, and upper abdominal pain) is then calculated
for each subject. Two additional symptoms (vomiting (frequency) and
bloating) are also analyzed by ANMS GCSI-DD. The severity scores of
the two symptoms (vomiting (frequency) and bloating) also range
from 0 (none) to 4 (very severe). An ANMS GCSI-DD composite score
(nausea, early satiety, postprandial fullness, upper abdominal
pain, bloating, and vomiting) is then calculated for each
subject.
[0123] Two additional instruments, PAGI-SYM (the Patient Assessment
of Upper Gastrointestinal Disorders-Symptom Severity Index) and
GEBT, are also used in the study. PAGI-SYM is a 20-item
self-reported questionnaire that measures symptom severity of upper
gastrointestinal disorders across six subscales (nausea/vomiting,
fullness/early satiety, bloating, upper abdominal pain, lower
abdominal pain, heartburn/regurgitation). GEBT is a nonradioactive,
noninvasive, orally administered test for measuring the rate of
solid phase gastric emptying (GE) in adults. GEBT measures how fast
solid food moves from the stomach to the small intestine during the
digestive process and aids in the diagnosis of delayed stomach
emptying (GP). GE half-emptying time is the time for half of the
ingested solids to leave the stomach. This value is measured by the
.sup.13C Spirulina GEBT.
[0124] The examples set forth above are provided to give those of
ordinary skill in the art with a complete disclosure and
description of how to make and use the claimed embodiments, and are
not intended to limit the scope of what is disclosed herein.
Modifications that are obvious to persons of skill in the art are
intended to be within the scope of the following claims. All
publications, patents, and patent applications cited in this
specification are incorporated herein by reference as if each such
publication, patent or patent application were specifically and
individually indicated to be incorporated herein by reference.
* * * * *