U.S. patent application number 17/104433 was filed with the patent office on 2021-10-21 for methods for treating subjects with prader-willi syndrome or smith-magenis syndrome.
The applicant listed for this patent is Essentialis, Inc.. Invention is credited to Neil M. COWEN.
Application Number | 20210322434 17/104433 |
Document ID | / |
Family ID | 1000005681865 |
Filed Date | 2021-10-21 |
United States Patent
Application |
20210322434 |
Kind Code |
A1 |
COWEN; Neil M. |
October 21, 2021 |
METHODS FOR TREATING SUBJECTS WITH PRADER-WILLI SYNDROME OR
SMITH-MAGENIS SYNDROME
Abstract
Provided are immediate or prolonged administration of certain
potassium ATP (KATP) channel openers, optionally in combination
with growth hormone, to a subject to achieve novel pharmacodynamic,
pharmacokinetic, therapeutic, physiological, metabolic and
compositional outcomes in the treatment of diseases or conditions
involving KATP channels. Also provided are pharmaceutical
formulations, methods of administration and dosing of KATP channel
openers that achieve these outcomes and reduce the incidence of
adverse effects in treated individuals. Further provided are
methods of co-administering KATP channel openers with other drugs
(e.g., in combination with growth hormone) to treat diseases of
humans and animals (e.g., Prader-Willi Syndrome (PWS),
Smith-Magenis syndrome (SMS), and the like.
Inventors: |
COWEN; Neil M.; (Carlsbad,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Essentialis, Inc. |
Redwood City |
CA |
US |
|
|
Family ID: |
1000005681865 |
Appl. No.: |
17/104433 |
Filed: |
November 25, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16573965 |
Sep 17, 2019 |
10874676 |
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17104433 |
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16041237 |
Jul 20, 2018 |
10456408 |
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16573965 |
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15671792 |
Aug 8, 2017 |
10058557 |
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16041237 |
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14940018 |
Nov 12, 2015 |
9757384 |
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15671792 |
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62221359 |
Sep 21, 2015 |
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62170035 |
Jun 2, 2015 |
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62138245 |
Mar 25, 2015 |
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62080150 |
Nov 14, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 9/5047 20130101; A61K 45/06 20130101; C07D 285/18 20130101;
A61K 31/549 20130101; A61K 9/00 20130101; A61K 31/155 20130101;
A61K 31/551 20130101; A61K 9/2054 20130101; A61K 9/5042 20130101;
A61K 9/5026 20130101; C07D 285/22 20130101; A61K 31/137 20130101;
A61K 9/0004 20130101; A61K 38/27 20130101 |
International
Class: |
A61K 31/549 20060101
A61K031/549; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20; A61K 9/50 20060101 A61K009/50; C07D 285/18 20060101
C07D285/18; C07D 285/22 20060101 C07D285/22; A61K 38/27 20060101
A61K038/27; A61K 45/06 20060101 A61K045/06; A61K 31/137 20060101
A61K031/137; A61K 31/155 20060101 A61K031/155; A61K 31/551 20060101
A61K031/551 |
Claims
1.-28. (canceled)
29. A kit comprising a pharmaceutical formulation, wherein the
pharmaceutical formulation comprises a K.sub.ATP channel opener,
wherein the kit is for treatment of hyperghrelinemia in a subject
having Prader-Willi syndrome (PWS) or Smith-Magenis syndrome
(SMS).
30. The kit of claim 29, wherein the K.sub.ATP channel opener is
diazoxide, or a pharmaceutically acceptable salt thereof.
31. The kit of claim 30, wherein the pharmaceutically acceptable
salt is diazoxide choline.
32. The kit of claim 29, wherein the pharmaceutical formulation is
administered once per day.
33. The kit of claim 29, wherein the pharmaceutical formulation is
administered twice per day.
34. The kit of claim 29, wherein the pharmaceutical formulation
comprises at least one excipient that affects the rate of release
of the K.sub.ATP channel opener or the pharmaceutically acceptable
salt thereof.
35. The kit of claim 29, wherein the pharmaceutical formulation
comprises at least one excipient that delays release of the
K.sub.ATP channel opener or the pharmaceutically acceptable salt
thereof.
36. The kit of claim 29, wherein the pharmaceutical formulation
comprises at least one other active ingredient.
37. The kit of claim 29, wherein the pharmaceutical formulation is
administered for 1 or more years.
38. The kit of claim 29, wherein the pharmaceutical formulation is
administered orally.
39. The kit of claim 29, wherein the subject is an adult.
40. The kit of claim 29, wherein the subject is over the age of
16.
41. The kit of claim 29, wherein the kit further comprises one or
more of a label, instructions, or reagents.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/573,965, filed Sep. 17, 2019, which is a
continuation of U.S. patent application Ser. No. 16/041,237, filed
Jul. 20, 2018, now U.S. Pat. No. 10,456,408, which is a
continuation of U.S. patent application Ser. No. 15/671,792, filed
Aug. 8, 2017, now U.S. Pat. No. 10,058,557, which is a divisional
of U.S. patent application Ser. No. 14/940,018, filed Nov. 12,
2015, now U.S. Pat. No. 9,757,384, which claims priority to U.S.
Provisional Patent Application No. 62/080,150, filed Nov. 14, 2014,
U.S. Provisional Patent Application No. 62/138,245, filed Mar. 25,
2015, U.S. Provisional Patent Application No. 62/170,035, filed
Jun. 2, 2015, and U.S. Provisional Patent Application No.
62/221,359, filed Sep. 21, 2015, each of which is incorporated
herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical formulations
of potassium ATP (K.sub.ATP) channel openers and their use for
treatment of various diseases and conditions such as Prader-Willi
Syndrome (PWS), Smith-Magenis syndrome (SMS), and the like.
BACKGROUND OF THE INVENTION
[0003] The following description of the background of the invention
is provided simply as an aid in understanding the invention and is
not admitted to describe or constitute prior art to the
invention.
[0004] ATP-sensitive potassium (K.sub.ATP) channels play important
roles in a variety of tissues by coupling cellular metabolism to
electrical activity. The K.sub.ATP channel has been identified as
an octameric complex of two unrelated proteins, which assemble in a
4:4 stoichiometry. The first is a pore forming subunit, Kir6.x,
which forms an inwardly rectifying K.sup.+ channel; the second is
an ABC (ATP binding cassette) transporter, also known as the
sulfonylurea receptor (SURx) (Babenko, et al., Annu. Rev. Physiol.,
60:667-687 (1998)). The Kir6.x pore forming subunit is common for
many types of K.sub.ATP channels, and has two putative
transmembrane domains (identified as TM1 and TM2), which are linked
by a pore loop (H5). The subunit that comprises the SUR receptor
includes multiple membrane-spanning domains and two
nucleotide-binding folds.
[0005] According to their tissue localization, K.sub.ATP channels
exist in different isoforms or subspecies resulting from the
assembly of the SUR and Kir subunits in multiple combinations. The
combination of the SUR1 with the Kir6.2 subunits (SUR1/Kir6.2)
typically forms the adipocyte and pancreatic B-cell type K.sub.ATP
channels, whereas the SUR2A/Kir6.2 and the SUR2B/Kir6.2 or Kir6.1
combinations typically form the cardiac type and the smooth muscle
type K.sub.ATP channels, respectively (Babenko, et al., Annu. Rev.
Physiol., 60:667-687 (1998)). There is also evidence that the
channel may include Kir2.x subunits. This class of potassium
channels are inhibited by intracellular ATP and activated by
intracellular nucleoside diphosphates. Such K.sub.ATP channels link
the metabolic status of the cells to the plasma membrane potential
and in this way play a key role in regulating cellular activity. In
most excitatory cells, K.sub.ATP channels are closed under normal
physiological conditions and open when the tissue is metabolically
compromised (e.g. when the (ATP:ADP) ratio falls). This promotes K+
efflux and cell hyperpolarization, thereby preventing
voltage-operated Ca2+ channels (VOCs) from opening. (Prog Res
Research, (2001) 31:77-80).
[0006] Potassium channel openers (PCOs or KCOs) (also referred to
as channel activators or channel agonists), are a structurally
diverse group of compounds with no apparent common pharmacophore
linking their ability to antagonize the inhibition of K.sub.ATP
channels by intracellular nucleotides. Diazoxide is a PCO that
stimulates K.sub.ATP channels in pancreatic .beta.-cells (see
Trube, et al., Pfluegers Arch kEur J Physiol, 407, 493-99 (1986)).
Pinacidil and chromakalim are PCOs that activate sarcolemmal
potassium channels (see Escande, et al., Biochem Biophys Res
Commun, 154, 620-625 (1988); Babenko, et al., J Biol Chem, 275(2),
717-720 (2000)). Responsiveness to diazoxide has been shown to
reside in the 6.sup.th through 11.sup.th predicted transmembrane
domains (TMD6-11) and the first nucleotide-binding fold (NBF1) of
the SUR1 subunit.
[0007] Diazoxide, which is a nondiuretic benzothiadiazine
derivative having the formula
7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1.1-dioxide (empirical
formula C.sub.8H.sub.7ClN.sub.2O.sub.2S), is commercialized in
three distinct formulations to treat two different disease
indications: 1) hypertensive emergencies and 2) hyperinsulinemic
hypoglycemic conditions. Hypertensive emergencies are treated with
Hyperstat IV, an aqueous formulation of diazoxide for intravenous
use, adjusted to pH 11.6 with sodium hydroxide. Hyperstat IV is
administered as a bolus dose into a peripheral vein to treat
malignant hypertension or sulfonylurea overdose. In this use,
diazoxide acts to open potassium channels in vascular smooth
muscle, stabilizing the membrane potential at the resting level,
and preventing vascular smooth muscle contraction.
[0008] Hyperinsulinemic hypoglycemic conditions are treated with
Proglycem, an oral pharmaceutical version of diazoxide useful for
administration to infants, children and adults. It is available as
a chocolate mint flavored oral suspension, which includes 7.25%
alcohol, sorbitol, chocolate cream flavor, propylene glycol,
magnesium aluminum silicate, carboxymethylcellulose sodium, mint
flavor, sodium benzoate, methylparaben, hydrochloric acid to adjust
the pH, poloxamer 188, propylparaben and water. Diazoxide is also
available as a capsule with 50 or 100 mg of diazoxide including
lactose and magnesium stearate.
[0009] Several experimental formulations of diazoxide have been
tested in humans and animals. These include an oral solution tested
in pharmacodynamic and pharmacokinetic studies and a tablet
formulation under development as an anti-hypertensive, but never
commercialized (see Calesnick, et al., J. Pharm. Sci. 54:1277-1280
(1965); Reddy, et al., AAPS Pharm Sci Tech 4(4):1-98, 9 (2003);
U.S. Pat. No. 6,361,795).
[0010] Current oral formulations of diazoxide are labeled for
dosing two or three times per day at 8 or 12 hour intervals. Most
patients receiving diazoxide are dosed three times per day.
Commercial and experimental formulations of diazoxide are
characterized by rapid drug release following ingestion with
completion of release in approximately 2 hours.
[0011] Current oral formulations of diazoxide in therapeutic use
result in a range of adverse side effects including dyspepsia,
nausea, diarrhea, fluid retention, edema, reduced rates of
excretion of sodium, chloride, and uric acid, hyperglycemia,
vomiting, abdominal pain, ileus, tachycardia, palpitations, and
headache (see current packaging insert for the Proglycem). Oral
treatment with diazoxide is used in individuals experiencing
serious disease where failing to treat results in significant
morbidity and mortality. The adverse side effects from oral
administration are tolerated because the benefits of treatment are
substantial. The adverse side effects profile of oral diazoxide
limit the utility of the drug in treating obese patients at doses
within the labeled range of 3 to 8 mg/kg per day.
[0012] The effect of diazoxide in animal models of diabetes and
obesity (e.g. obese and lean Zucker rats) has been reported. See
e.g. Alemzadeh et al. (Endocrinology 133:705-712 (1993), Alemzadeh
et al. (Metabolism 45:334-341 (1996)), Alemzadeh et al.
(Endocrinology 140:3197-3202 (1999)), Stanridge et al. (FASEB J
14:455-460 (2000)), Alemzadeh et al. (Med Sci Monit 10(3): BR53-60
(2004)), Alemzadeh and Tushaus (Endocrinology 145(12):3476-3484
(2004)), Aizawa et al. (J of Pharma Exp Ther 275(1): 194-199
(1995)), and Surwit et al. (Endocrinology 141:3630-3637
(2000)).
[0013] The effect of diazoxide in humans with obesity or diabetes
has been reported. See e.g., Wigand and Blackard (Diabetes
28(4):287-291 (1979); evaluation of diazoxide on insulin
receptors), Ratzmann et al. (Int J Obesity 7(5):453-458 (1983);
glucose tolerance and insulin sensitivity in moderately obese
patients), Marugo et al. (Boll Spec It Biol Sper 53:1860-1866
(1977); moderate dose diazoxide treatment on weight loss in obese
patients), Alemzadeh et al. (J Clin Endocr Metab 83:1911-1915
(1998); low dose diazoxide treatment on weight loss in obese
hyperinsulinemic patients), Guldstrand et al. (Diabetes and
Metabolism 28:448-456 (2002); diazoxide in obese type II diabetic
patients), Ortqvist et al. (Diabetes Care 27(9):2191-2197 (2004);
beta-cell function measured by circulating C-peptide in children at
clinical onset of type 1 diabetes), Bjork et al. (Diabetes Care
21(3):427-430 (1998); effect of diazoxide on residual insulin
secretion in adult type I diabetes patients), and Qvigstad et al.,
(Diabetic Medicine 21:73-76 (2004)).
[0014] U.S. Pat. No. 5,284,845 describes a method for normalizing
blood glucose and insulin levels in an individual exhibiting normal
fasting blood glucose and insulin levels and exhibiting in an oral
glucose tolerance test, elevated glucose levels and at least one
insulin level abnormality selected from the group consisting of a
delayed insulin peak, an exaggerated insulin peak and a secondary
elevated insulin peak. According to this reference, the method
includes administering diazoxide in an amount from about 0.4 to
about 0.8 mg/kg body weight before each meal in an amount effective
to normalize the blood glucose and insulin levels.
[0015] U.S. Pat. No. 6,197,765 describes administration of
diazoxide as a treatment for syndrome-X, and resulting
complications, that include hyperlipidemia, hypertension, central
obesity, hyperinsulinemia and impaired glucose intolerance.
According to this reference, diazoxide interferes with pancreatic
islet function by ablating endogenous insulin secretion resulting
in a state of insulin deficiency and high blood glucose levels
equivalent to that of diabetic patients that depend on exogenous
insulin administration for normalization of their blood glucose
levels.
[0016] U.S. Pat. No. 2,986,573 describes diazoxide and alkali metal
salts for the treatment of hypertension.
[0017] U.S. Pat. No. 5,629,045 describes diazoxide for topical
ophthalmic administration.
[0018] WO 98/10786 describes use of diazoxide in the treatment of
X-syndrome including obesity associated therewith.
[0019] U.S. Patent publication no. 2003/0035106 describes
diazoxide-containing compounds for reducing the consumption of
fat-containing foods.
[0020] U.S. Patent publication no. 2004/0204472 describes the use
of a Cox-2 inhibitor plus diazoxide in the treatment of
obesity.
[0021] U.S. Patent publication no. 2002/0035106 describes the use
of K.sub.ATP channel openers including diazoxide and metal salts
for reducing the consumption of fat containing food.
SUMMARY OF THE INVENTION
[0022] Provided herein are pharmaceutical formulations of K.sub.ATP
channel openers and their use (optionally in combination with
growth hormone) for treatment of various diseases and conditions,
including Prader-Willi Syndrome (PWS), Smith-Magenis syndrome
(SMS), and the like. Such formulations are characterized as being
bioavailable. A K.sub.ATP channel opener as used herein has any one
or more of the following properties: (1) opening SUR1/Kir6.2
potassium channels; (2) binding to the SUR1 subunit of K.sub.ATP
channels; and (3) inhibiting glucose induced release of insulin
following administration of the compound in vivo. Preferably,
K.sub.ATP channel openers are K.sub.ATP channel openers with all
three properties. K.sub.ATP channel openers as defined above
preferably have the structure of compounds of Formulas I-VII as set
forth below.
[0023] In accordance with one aspect of the present invention, it
has been discovered that one or more K.sub.ATP channel opener(s)
(optionally in combination with growth hormone) is effective for
the treatment of a subject having Prader-Willi Syndrome (PWS),
Smith-Magenis syndrome (SMS), and the like, and is especially
effective for increasing the lean body mass of such subjects.
Therefore, in one aspect of the present invention, there are
provided methods of increasing the lean body mass of a subject
having Prader-Willi Syndrome (PWS), Smith-Magenis syndrome (SMS),
and the like, said method comprising administering to said subject
for at least 4 weeks an effective amount of a K.sub.ATP channel
opener (optionally in combination with growth hormone).
[0024] In some embodiments, the lean body mass of said subject is
increased by at least 1%. In some embodiments, the lean body mass
of said subject is increased by at least 2%. In some embodiments,
the lean body mass of said subject is increased by at least 3%. In
some embodiments, the lean body mass of said subject is increased
by at least 4%. In some embodiments, the lean body mass of said
subject is increased by at least 5%.
[0025] In addition to increasing the lean body mass of a subject,
in some embodiments, invention methods also reduce the hyperphagia
of a subject. In some embodiments, the hyperphagia of said subject
is reduced by at least 10%. In some embodiments, the hyperphagia of
said subject is reduced by at least 20%. In some embodiments, the
hyperphagia of said subject is reduced by at least 30%.
[0026] In addition to increasing the lean body mass of a subject,
in some embodiments, invention methods also reduce the body fat of
a subject. In some embodiments, the body fat of said subject is
reduced by at least 1%. In some embodiments, the body fat of said
subject is reduced by at least 3%. In some embodiments, the body
fat of said subject is reduced by at least 5%.
[0027] In another aspect, the present invention provides a method
of increasing the lean body mass of a subject having Prader-Willi
Syndrome (PWS), Smith-Magenis syndrome (SMS), and the like, wherein
said subject is already being treated by administration thereto of
growth hormone, said method comprising co-administering to said
subject an effective amount of a K.sub.ATP channel opener in
addition to said growth hormone.
[0028] In yet another aspect, the present invention provides a
method of increasing the lean body mass of a subject having
Prader-Willi Syndrome (PWS), Smith-Magenis syndrome (SMS), and the
like, wherein said subject is already being treated by
administration thereto of an effective amount of a K.sub.ATP
channel opener, said method comprising co-administering to said
subject an effective amount of growth hormone in addition to said
K.sub.ATP channel opener.
[0029] K.sub.ATP channel openers defined by Formula I are as
follows:
##STR00001##
wherein: [0030] R.sup.1a and R.sup.1b, when present, are
independently selected from the group consisting of hydrogen, lower
alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,
amino, and substituted amino; [0031] R.sup.2a and R.sup.2b, when
present, are independently selected from the group consisting of
hydrogen, and lower alkyl; [0032] X is a 1, 2 or 3 atom chain,
wherein each atom is independently selected from carbon, sulfur or
nitrogen, and each atom is optionally substituted with halogen,
hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy,
cycloalkyl, substituted cycloalkyl, substituted lower alkoxy,
amino, or substituted amino; [0033] wherein rings A and B are each
independently saturated, monounsaturated, polyunsaturated or
aromatic; [0034] and all bioequivalents including salts, prodrugs
and isomers thereof.
[0035] In particular embodiments, compounds of Formula I may
include a double bond between either positions 1 and 2 or positions
2 and 3 of Ring A. When a double bond is present between positions
1 and 2 of Ring A, R.sup.2a is absent and one of R.sup.1a and
R.sup.1b are absent. When a double bond is present between
positions 2 and 3 of Ring A, R.sup.2b is absent and one of R.sup.1a
and R.sup.1b are absent. In a preferred embodiment, R.sup.1a and
R.sup.1b are not amino. In another preferred embodiment, Ring B
does not include any heteroatoms.
[0036] K.sub.ATP channel openers defined by Formula II being a
subgenera of Formula I are as follows:
##STR00002##
wherein: [0037] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl,
substituted cycloalkyl, amino, and substituted amino; [0038]
R.sup.2a is selected from the group consisting of hydrogen, and
lower alkyl; [0039] X is a 1, 2 or 3 atom chain, wherein each atom
is independently selected from carbon, sulfur or nitrogen, and each
atom is optionally substituted with halogen, hydroxyl, lower alkyl,
substituted lower alkyl, lower alkoxy, cycloalkyl, substituted
cycloalkyl, substituted lower alkoxy, amino, or substituted amino;
[0040] wherein ring B is saturated, monounsaturated,
polyunsaturated or aromatic; [0041] and all bioequivalents
including salts, prodrugs and isomers thereof.
[0042] In particular embodiments of Formula II, X is
C(R.sup.a)C(R.sup.b), wherein R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen, halogen, lower
alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,
lower alkoxy, substituted lower alkoxy, amino, sulfonylamino,
aminosulfonyl, sulfonyl, and the like. In further embodiments,
R.sup.a and R.sup.b are independently selected from the group
consisting of hydroxyl, substituted oxy, substituted thiol,
alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted
sulfinyl, substituted sulfonyl, substituted sulfonylamino,
substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl,
alkylsulfonylamino, and the like. In a preferred embodiment,
R.sup.1 is not amino. In another preferred embodiment, Ring B does
not include any heteroatoms.
[0043] K.sub.ATP channel openers defined by Formula III being a
subgenera of Formula I are as follows:
##STR00003##
wherein: [0044] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl,
substituted cycloalkyl, amino, and substituted amino; [0045]
R.sup.2b is selected from the group consisting of hydrogen, and
lower alkyl; [0046] X is a 1, 2 or 3 atom chain, wherein each atom
is independently selected from carbon, sulfur or nitrogen, and each
atom is optionally substituted with halogen, hydroxyl, lower alkyl,
substituted lower alkyl, lower alkoxy, cycloalkyl, substituted
cycloalkyl, substituted lower alkoxy, amino, or substituted amino;
[0047] wherein ring B is saturated, monounsaturated,
polyunsaturated or aromatic; [0048] and all bioequivalents
including salts, prodrugs and isomers thereof.
[0049] In particular embodiments of Formula III, X is
C(R.sup.a)C(R.sup.b), wherein R.sup.a and R.sup.b are independently
selected from the group consisting of hydrogen, halogen, lower
alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,
lower alkoxy, substituted lower alkoxy, amino, sulfonylamino,
aminosulfonyl, sulfonyl, and the like. In further embodiments,
R.sup.a and R.sup.b are independently selected from the group
consisting of hydroxyl, substituted oxy, substituted thiol,
alkylthio, substituted alkylthio, sulfinyl, sulfonyl, substituted
sulfinyl, substituted sulfonyl, substituted sulfonylamino,
substituted amino, substituted amine, alkylsulfinyl, alkylsulfonyl,
alkylsulfonylamino, and the like. In a preferred embodiment,
R.sup.1 is not amino. In another preferred embodiment, Ring B does
not include any heteroatoms.
[0050] K.sub.ATP channel openers defined by Formula IV being a
subgenera of Formula I are as follows:
##STR00004##
wherein: [0051] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino,
and substituted lower amino; [0052] R.sup.2a is selected from the
group consisting of hydrogen, lower alkyl, and substituted lower
alkyl; [0053] R.sup.3 is selected from the group consisting of
hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and
substituted amino; [0054] R.sup.4 is selected from the group
consisting of hydrogen, halogen, lower alkyl, substituted lower
alkyl, amino, and substituted amino; [0055] and all bioequivalents
including salts, prodrugs and isomers thereof.
[0056] In particular embodiments of Formula IV, R.sup.1 is a lower
alkyl (preferably ethyl or methyl); R.sup.2a is hydrogen; and
R.sup.3 and R.sup.4 are each independently halogen.
[0057] In a preferred embodiment of Formula IV, R.sup.1 is not
amino.
[0058] In another embodiment of Formula IV, R.sup.1 is methyl;
R.sup.2a is hydrogen; R.sup.3 is selected from the group consisting
of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino,
substituted amino, cycloalkyl, and substituted cycloalkyl; and
R.sup.4 is chlorine.
[0059] K.sub.ATP channel openers defined by Formula V being a
subgenera of Formula I are as follows:
##STR00005##
wherein: [0060] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl, amino,
and substituted lower amino; [0061] R.sup.2b is selected from the
group consisting of hydrogen, lower alkyl, and substituted lower
alkyl; [0062] R.sup.3 is selected from the group consisting of
hydrogen, halogen, lower alkyl, substituted lower alkyl, amino, and
substituted amino; [0063] R.sup.4 is selected from the group
consisting of hydrogen, halogen, lower alkyl, substituted lower
alkyl, amino, and substituted amino; [0064] and all bioequivalents
including salts, prodrugs and isomers thereof.
[0065] In particular embodiments of Formula V, R.sup.1 is a lower
alkyl (preferably ethyl or methyl); R.sup.2b is hydrogen; and
R.sup.3 and R.sup.4 are each independently halogen.
[0066] In a preferred embodiment of Formula V, R.sup.1 is not
amino.
[0067] In another embodiment of Formula V, R.sup.1 is methyl;
R.sup.2b is hydrogen; R.sup.3 is selected from the group consisting
of hydrogen, halogen, lower alkyl, substituted lower alkyl, amino,
substituted amino, cycloalkyl, and substituted cycloalkyl; and
R.sup.4 is chlorine.
[0068] K.sub.ATP channel openers defined by Formula VI are as
follows:
##STR00006##
wherein: [0069] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl,
substituted cycloalkyl, amino, and substituted lower amino, or
R.sup.1 can cooperate with R.sup.5 or R.sup.6 to form an additional
ring; [0070] R.sup.2a is selected from the group consisting of
hydrogen, lower alkyl, and substituted lower alkyl; [0071] R.sup.5
is selected from the group consisting of hydrogen, halogen,
hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted
amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R.sup.5 can
cooperate with R.sup.1 or R.sup.6 to form an additional ring;
[0072] R.sup.6 is selected from the group consisting of hydrogen,
halogen, lower alkyl, substituted lower alkyl, amino, substituted
amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R.sup.6 can
cooperate with R.sup.1 or R.sup.5 to form an additional ring;
[0073] wherein the ring formed by the cooperation of R.sup.1 and
R.sup.5, or R.sup.1 and R.sup.6, or R.sup.5 and R.sup.6 is
saturated, monounsaturated, polyunsaturated or aromatic; [0074]
wherein the ring formed by the cooperation of R.sup.1 and R.sup.5,
or R.sup.1 and R.sup.6, or R.sup.5 and R.sup.6 is optionally
substituted with halogen, hydroxyl, lower alkyl, substituted lower
alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or
sulfonylamino; [0075] and all bioequivalents including salts,
prodrugs and isomers thereof.
[0076] In a preferred embodiment, R.sup.1 is not an amino
substituent.
[0077] In another embodiment of Formula VI, R.sup.5 and R.sup.6
combine to form a 6 membered ring. In another embodiment, R.sup.5
and R.sup.6 combine to form a 6 membered ring wherein at least one
nitrogen is present. Preferably, the ring formed by R.sup.5 and
R.sup.6 does not include any heteroatoms.
[0078] K.sub.ATP channel openers defined by Formula VII are as
follows:
##STR00007##
wherein: [0079] R.sup.1 is selected from the group consisting of
hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl,
substituted cycloalkyl, amino, and substituted lower amino, or
R.sup.1 can cooperate with R.sup.5 or R.sup.6 to form an additional
ring; [0080] R.sup.2b is selected from the group consisting of
hydrogen, lower alkyl, and substituted lower alkyl; [0081] R.sup.5
is selected from the group consisting of hydrogen, halogen,
hydroxyl, lower alkyl, substituted lower alkyl, amino, substituted
amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R.sup.5 can
cooperate with R.sup.1 or R.sup.6 to form an additional ring;
[0082] R.sup.6 is selected from the group consisting of hydrogen,
halogen, lower alkyl, substituted lower alkyl, amino, substituted
amino, sulfonyl, aminosulfonyl, and sulfonylamino, or R.sup.6 can
cooperate with R.sup.1 or R.sup.5 to form an additional ring;
[0083] wherein the ring formed by the cooperation of R.sup.1 and
R.sup.5, or R.sup.1 and R.sup.6, or R.sup.5 and R.sup.6 is
saturated, monounsaturated, polyunsaturated or aromatic; [0084]
wherein the ring formed by the cooperation of R.sup.1 and R.sup.5,
or R.sup.1 and R.sup.6, or R.sup.5 and R.sup.6 is optionally
substituted with halogen, hydroxyl, lower alkyl, substituted lower
alkyl, amino, substituted amino, sulfonyl, aminosulfonyl, or
sulfonylamino; [0085] and all bioequivalents including salts,
prodrugs and isomers thereof.
[0086] In a preferred embodiment, R.sup.1 is not an amino
substituent.
[0087] In another embodiment of Formula VI, R.sup.5 and R.sup.6
combine to form a 6 membered ring. In another embodiment, R.sup.5
and R.sup.6 combine to form a 6 membered ring wherein at least one
nitrogen is present. Preferably, the ring formed by R.sup.5 and
R.sup.6 does not include any heteroatoms.
[0088] Unless otherwise indicated, reference in this application to
K.sub.ATP channel openers should be understood to refer to
K.sub.ATP channel opener(s) having one or more and preferably all
three of the following properties: (1) opening SUR1/Kir6.2
potassium channels; (2) binding to the SUR1 subunit of K.sub.ATP
channels; and (3) inhibiting glucose induced release of insulin
following administration of the compound in vivo. Such K.sub.ATP
channel openers preferably have the structure of any of the
compounds of Formulae I-VII, or more preferably Formulae I-VII
where R.sup.1 is not amino and also where ring B or its equivalent
does not include any heteroatoms, or more preferably, any of the
compounds of Formulae II or III, or more preferably, any of the
compounds of Formulae II or III where R.sup.1 is not amino and also
where ring B or its equivalent does not include any heteroatoms, or
more preferably, the structure is diazoxide. Structural variants or
bioequivalents of the compounds of any of Formulae I-VII such as
derivatives, salts, prodrugs or isomers are also contemplated.
Other K.sub.ATP channel openers that are contemplated for use
herein include BPDZ62, BPDZ 73, NN414, BPDZ 154.
[0089] In vitro analysis of glucose induced release of insulin via
K.sub.ATP channel openers can be determined using rat islets as
provided by De Tullio, et al., J. Med. Chem., 46:3342-3353 (2003)
or by using human islets as provided by Bjorklund, et al.,
Diabetes, 49:1840-1848 (2000).
[0090] Provided herein are formulations, such as controlled release
pharmaceutical formulations, of K.sub.ATP channel openers and
bioquivalents thereof. In one embodiment, the controlled release
formulations are formulated for oral administration. Such
formulations contain in a single administration dosage between 10
and 100 mg, between 25 and 100 mg, between 100 and 200 mg, between
200 and 300 mg, between 300 and 500 mg or between 500 and 2000 mg
of the K.sub.ATP channel openers. In certain embodiments, the
dosage of the K.sub.ATP channel openers contained in a formulation
may be determined based on the weight of the patient for which it
is to be administered, i.e., the formulation may contain in a
single administration dosage between 0.1-20 mg of the K.sub.ATP
channel opener per kg of the patient's body weight, or between
0.1-0.5 mg of the K.sub.ATP channel opener per kg of the patient's
body weight; or between 0.5-1 mg of the K.sub.ATP channel opener
per kg of the patient's body weight; or between 1-2 mg of the
K.sub.ATP channel opener per kg of the patient's body weight, or
between 2-5 mg of the K.sub.ATP channel opener per kg of the
patient's body weight, or between 5-10 mg of the K.sub.ATP channel
opener per kg of the patient's body weight, or between 10-15 mg of
the K.sub.ATP channel opener per kg of the patient's body weight,
or between 15-20 mg of the K.sub.ATP channel opener per kg of the
patient's body weight.
[0091] Also provided herein are controlled release pharmaceutical
formulations containing K.sub.ATP channel openers obtained by at
least one of the following: (a) particle size reduction involving
comminution, spray drying, or other micronising techniques, (b) use
of a pharmaceutical salt of the K.sub.ATP channel opener, (c) use
of an ion exchange resin, (d) use of inclusion complexes, for
example cyclodextrin, (e) compaction of the K.sub.ATP channel
opener with a solubilizing agent including a low viscosity
hypromellose, low viscosity metylcellulose or similarly functioning
excipient or combinations thereof, (f) associating the K.sub.ATP
channel opener with a salt prior to formulation, (g) use of a solid
dispersion of the K.sub.ATP channel opener, (h) use of a self
emulsifying system, (i) addition of one or more surfactants to the
formulation, (j) use of nanoparticles, or (k) combinations of these
approaches.
[0092] Further provided herein are controlled release
pharmaceutical formulations containing K.sub.ATP channel openers
which include at least one component that substantially inhibits
release of the K.sub.ATP channel activator from the formulation
until after gastric transit. As used herein, "substantially
inhibits" means less than 15% release, more preferably at least
less than 10% release, or more preferably at least less than 5%
release of the drug from the formulation during gastric transport.
Release can be measured in a standard USP based in-vitro gastric
dissolution assay in a calibrated dissolution apparatus (see, for
example, U.S. Pharmacopeia, Chapter 711 (2005)).
[0093] Also provided are oral pharmaceutical formulations of
K.sub.ATP channel openers which include at least one component that
substantially inhibits release of the K.sub.ATP channel opener from
the formulation until after gastric transit. Substantial inhibition
of drug release during gastric transit is achieved by inclusion of
a component in the formulation selected from the group consisting
of: (a) a pH sensitive polymer or co-polymer applied as a
compression coating on a tablet, (b) a pH sensitive polymer or
co-polymer applied as a thin film on a tablet, (c) a pH sensitive
polymer or co-polymer applied as a thin film to an encapsulation
system, (d) a pH sensitive polymer or co-polymer applied to
encapsulated microparticles, (e) a non-aqueous-soluble polymer or
co-polymer applied as a compression coating on a tablet, (f) a
non-aqueous-soluble polymer or co-polymer applied as a thin film on
a tablet, (g) a non-aqueous soluble polymer applied as a thin film
to an encapsulation system, (h) a non-aqueous soluble polymer
applied to microparticles, (i) incorporation of the formulation in
an osmotic pump system, (j) use of systems controlled by ion
exchange resins, and (k) combinations of these approaches, wherein
the pH sensitive polymer or co-polymer is resistant to degradation
under acid conditions.
[0094] Also provided herein are controlled release pharmaceutical
formulations of K.sub.ATP channel openers, wherein the formulation
includes at least one component that contributes to sustained
release of a K.sub.ATP channel opener over a period of 2-4 hours
following administration, or over a period of 4-8 hours following
administration, or over a period of more than 8-24 hours following
administration. These formulations are characterized in having one
of the following components: (a) a pH sensitive polymeric coating,
(b) a hydrogel coating, (c) a film coating that controls the rate
of diffusion of the drug from a coated matrix, (d) an erodable
matrix that controls rate of drug release, (e) polymer coated
pellets, granules or microparticles of drug which can be further
encapsulated or compressed into a tablet, (f) an osmotic pump
system containing the drug, (g) a compression coated tablet form of
the drug, or (h) combinations of these approaches.
[0095] As used herein, an erodable matrix is the core of a tablet
formulation that, upon exposure to an aqueous environment, begins a
process of disintegration which facilitates the release of drug
from the matrix. The rate of release of drug from the tablet is
controlled both by the solubility of the drug and the rate of
disintegration of the matrix.
[0096] The above formulations may further comprise one or more
additional pharmaceutically active agents (other than K.sub.ATP
channel openers) useful for the treatment of a condition selected
from the group consisting of obesity, prediabetes, diabetes,
hypertension, depression, elevated cholesterol, fluid retention,
other obesity associated comorbidities, ischemic and reperfusion
injury, epilepsy, schizophrenia, mania, or other psychotic
diseases.
[0097] Further provided is a controlled release pharmaceutical
formulation of a K.sub.ATP channel opener wherein administration to
an obese, overweight or obesity prone individual results in at
least one of the following: (a) inhibition of fasting insulin
secretion (b) inhibition of stimulated insulin secretion, (c)
elevation of energy expenditure, (d) elevation of beta oxidation of
fat, (e) inhibition of hyperphagia for about 24 hours, or (f)
increase in lean body mass.
[0098] Additionally provided is a controlled release pharmaceutical
formulation of a K.sub.ATP channel opener wherein administration to
an obese, overweight or obesity prone individual results in at
least one of the following: (a) inhibition of fasting insulin
secretion (b) inhibition of glucose stimulated insulin secretion,
(c) elevation of energy expenditure, (d) elevation of beta
oxidation of fat, (e) inhibition of hyperphagia for about 18 hours,
or (f) increase in lean body mass.
[0099] Still further provided is a controlled release
pharmaceutical formulation of a K.sub.ATP channel opener which upon
administration to an obese, overweight or obesity prone individual
results in at least one of the following: (a) inhibition of fasting
insulin secretion (b) inhibition of glucose stimulated insulin
secretion, (c) elevation of energy expenditure, (d) elevation of
beta oxidation of fat, (e) inhibition of hyperphagia for about 24
hours, or (f) increase in lean body mass.
[0100] Additionally provided is a controlled release pharmaceutical
formulation of a K.sub.ATP channel opener that upon administration
to an obese, overweight or obesity prone individual results in at
least one of the following: (a) inhibition of fasting insulin
secretion (b) inhibition of glucose stimulated insulin secretion,
(c) elevation of energy expenditure, (d) elevation of beta
oxidation of fat, (e) inhibition of hyperphagia for about 18 hours,
or (f) increase in lean body mass.
[0101] Provided herein is a method of treating hypoglycemia, the
method comprising orally administering a controlled release
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone.
[0102] Further provided herein is a method of treating obesity
associated co-morbidities in an obese, overweight or obesity prone
individual, the method comprising administering a therapeutically
effective amount of a solid oral dosage form of a K.sub.ATP channel
opener, or controlled release pharmaceutical formulation of a
K.sub.ATP channel opener, optionally in combination with growth
hormone. In a preferred embodiment, administration is no more than
two times per 24 hours, or once per 24 hours.
[0103] Yet further provided herein is a method of achieving weight
loss in an obese overweight, or obesity prone individual, the
method comprising administering a therapeutically effective amount
of a solid oral dosage form of a K.sub.ATP channel opener or
controlled release pharmaceutical formulation of a K.sub.ATP
channel opener, optionally in combination with growth hormone. In a
preferred embodiment, administration is no more than two times per
24 hours, or once per 24 hours. The daily dosage administered is
preferably between 50 and 180 mg. In certain embodiments, the obese
individual has a body mass index greater than 30 kg/m.sup.2, or
greater than 35 kg/m.sup.2, or greater than 40 kg/m.sup.2, or
greater than 50 kg/m.sup.2, or greater than 60 kg/m.sup.2 at the
time the method commences.
[0104] Also provided is a method of maintaining a weight loss in an
obese overweight, or obesity prone individual, the method
comprising administering a therapeutically effective amount of a
solid oral dosage form of a K.sub.ATP channel opener or controlled
release pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. It is preferable to
maintain weight in an obese individual once some weight loss has
occurred when the alternative is to regain weight. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours.
[0105] Further provided is a method of elevating energy expenditure
in an overweight, obese or obesity prone individual, the method
comprising administering an effective amount of a solid oral dosage
form of a K.sub.ATP channel opener or controlled release
pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours. In certain embodiments, the individual has a
body mass index greater than 20 kg/m.sup.2, or greater than 25
kg/m.sup.2, or greater than 30 kg/m.sup.2, or greater than 35
kg/m.sup.2, or greater than 40 kg/m.sup.2, or greater than 50
kg/m.sup.2, or greater than 60 kg/m.sup.2 at the time the method
commences.
[0106] Additionally provided is a method of elevating beta
oxidation of fat in an overweight, obese or obesity prone
individual, the method comprising administering an effective amount
of a solid oral dosage form of a K.sub.ATP channel opener or
controlled release pharmaceutical formulation of a K.sub.ATP
channel opener, optionally in combination with growth hormone. In a
preferred embodiment, administration is no more than two times per
24 hours, or once per 24 hours. In certain embodiments, the
individual has a body mass index greater than 20 kg/m.sup.2, or
greater than 25 kg/m.sup.2, or greater than 30 kg/m.sup.2, or
greater than 35 kg/m.sup.2, or greater than 40 kg/m.sup.2, or
greater than 50 kg/m.sup.2, or greater than 60 kg/m.sup.2 at the
time the method commences.
[0107] Yet further provided is a method of reducing visceral fat in
an overweight, obese or obesity prone individual, the method
comprising administering an effective amount of a solid oral dosage
form of a K.sub.ATP channel opener or controlled release
pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours.
[0108] Still further provided is a method of delaying or preventing
the transition to diabetes of a prediabetic individual comprising
administering an effective amount of a K.sub.ATP channel opener or
controlled release pharmaceutical formulation of a K.sub.ATP
channel opener, optionally in combination with growth hormone. In a
preferred embodiment, administration is no more than two times per
24 hours, or once per 24 hours.
[0109] Additionally provided is a method of restoring normal
glucose tolerance in a prediabetic individual comprising
administering an effective amount of a K.sub.ATP channel opener or
controlled release pharmaceutical formulation of a K.sub.ATP
channel opener, optionally in combination with growth hormone. In a
preferred embodiment, administration is no more than two times per
24 hours, or once per 24 hours.
[0110] Further provided is a method of restoring normal glucose
tolerance in a diabetic individual comprising administering an
effective amount of a K.sub.ATP channel opener or controlled
release pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours.
[0111] Still further provided is a method of delaying or preventing
progression of diabetes in an individual comprising administering
an effective amount of a K.sub.ATP channel opener or controlled
release pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours.
[0112] Also provided is a method to prevent or treat weight gain,
impaired glucose tolerance or dyslipidemia associated with the use
of anti-psychotics to treat patients comprising the
co-administration of an effective amount of a K.sub.ATP channel
opener or controlled release pharmaceutical formulation of a
K.sub.ATP channel opener, optionally in combination with growth
hormone. In a preferred embodiment, administration is no more than
two times per 24 hours, or once per 24 hours.
[0113] Further provided is a method to increase lean body mass in a
Prader-Willi Syndrome patient, in a Smith-Magenis syndrome patient,
in a Froelich's Syndrome patient, in a Cohen Syndrome patient, in a
Summit Syndrome patient, in an Alstrom Syndrome patient, in a
Borjeson Syndrome patient or in a Bardet-Biedl Syndrome patient
comprising the administration of an effective amount of a K.sub.ATP
channel opener (optionally in combination with growth hormone) or a
controlled release pharmaceutical formulation of a K.sub.ATP
channel opener (optionally in combination with growth hormone). In
a preferred embodiment, administration is no more than two times
per 24 hours, or once per 24 hours.
[0114] Still further provided is a method to treat obesity or
elevated triglycerides in a patient suffering hyperlipoproteinemia
type I, type II, type III or type IV comprising administering an
effective amount of a K.sub.ATP channel opener or controlled
release pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone. In a preferred
embodiment, administration is no more than two times per 24 hours,
or once per 24 hours.
[0115] Also provided is a method of reducing the incidence of
adverse effects from administration of a K.sub.ATP channel opener
in the treatment of diseases of a subject achieved by any of the
following: (a) use of a dosage form that on administration reduces
C.sub.max relative to the current Proglycem oral suspension or
capsule products in order to reduce the incidence of adverse side
effects that are associated with peak drug levels, (b) use of a
dosage form that delays release until gastric transit is complete
in order to reduce the incidence of adverse side effects that are
associated with the release of drug in the stomach, (c) initiating
dosing at subtherapeutic levels and in a stepwise manner increasing
dose daily until the therapeutic dose is achieved wherein the
number of steps is 2 to 10 to reduce the incidence of adverse side
effects that occur transiently at the initiation of treatment, (d)
use of the lowest effective dose to achieve the desired therapeutic
effect in order to reduce the incidence of adverse side effects
that are dose dependent, or (e) optimizing the timing of
administration of dose within the day and relative to meals.
[0116] Further provided is a method of preventing weight gain,
dyslipidemia or impaired glucose tolerance in a subject treated
with an anti-psychotic drug, the method comprising administering a
pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone.
[0117] Yet further provided is a method of treating weight gain,
dyslipidemia or impaired glucose tolerance in a subject treated
with an anti-psychotic drug, the method comprising administering a
pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone.
[0118] Also provided is a method of treating diseases characterized
by obesity, hyperphagia, dyslipidemia, or decreased energy
expenditure including (a) Prader Willi Syndrome, (b) Froelich's
syndrome, (c) Cohen syndrome, (d) Summit Syndrome, (e) Alstrom,
Syndrome, (f) Borjesen Syndrome, (g) Bardet-Biedl Syndrome, (h)
hyperlipoproteinemia type I, II, III, and IV, or (i) Smith-Magenis
syndrome (SMS), said method comprising administering a
pharmaceutical formulation of a K.sub.ATP channel opener,
optionally in combination with growth hormone.
[0119] Further provided is a pharmaceutical formulation of a
K.sub.ATP channel opener further comprising a pharmaceutically
active agent other than the K.sub.ATP channel opener. In this
formulation, the other pharmaceutically active agent is an agent
useful for the treatment of a condition selected from the group
consisting of obesity, prediabetes, diabetes, hypertension,
depression, elevated cholesterol, fluid retention, or other obesity
associated comorbidities, ischemic and reperfusion injury,
epilepsy, schizophrenia, mania, and other psychotic condition.
[0120] The formulations containing K.sub.ATP channel openers
described herein provide for improved compliance, efficacy and
safety, and for co-formulations with other agents. Included are
co-formulations of K.sub.ATP channel openers with one or more
additional pharmaceutically active agents that have complementary
or similar activities or targets. Other pharmaceutical active
agents that can be combined with K.sub.ATP channel openers to treat
obesity or to maintain weight loss in an obesity prone individual
include, but are not limited to: sibutramine, orlistat,
phentermine, rimonabant, a diuretic, an antiepileptic, or other
pharmaceutical active whose therapeutic utility includes weight
loss. It is preferable to maintain weight in an obese individual
once some weight loss has occurred when the alternative is to
regain weight. Other pharmaceutically active agents that may be
combined with K.sub.ATP channel openers to treat type II diabetes,
or prediabetes include acarbose, miglitol, metformin, repaglinide,
nateglinide, rosiglitizone, proglitizone, ramipril, metaglidasen,
or any other pharmaceutical active that improves insulin
sensitivity or glucose utilization or glycemic control where the
mode of action is not enhanced insulin secretion. Other
pharmaceutical active agents that can be combined with K.sub.ATP
channel openers to treat obesity associated co-morbidities include
a drug active used to lower cholesterol, a drug active used to
lower blood pressure, an anti-inflammatory drug that is not a cox-2
inhibitor, a drug that is an antidepressant, a drug used to treat
urinary incontinence, or other drug routinely used to treat disease
conditions the incidence of which is elevated in overweight or
obese patients as compared to normal weight individuals including,
but not limited to, drugs to treat atherosclerosis, osteoarthritis,
disc herniation, degeneration of knees and hips, breast,
endometrium, cervical, colon, leukemia and prostate cancers,
hyperlipidemia, asthma/reactive airway disease, gallstones, GERD,
obstructive sleep apnea, obesity hypoventilation syndrome,
recurrent ventral hernias, menstrual irregularity, infertility, and
the like.
[0121] In the present context, the term "therapeutically effective"
or "effective amount" indicates that the materials or amount of
material is effective to prevent, alleviate, or ameliorate one or
more symptoms of a disease or medical condition, and/or to prolong
the survival of the subject being treated.
[0122] The term "pharmaceutically acceptable" indicates that the
identified material does not have properties that would cause a
reasonably prudent medical practitioner to avoid administration of
the material to a patient, taking into consideration the disease or
conditions to be treated and the respective route of
administration. For example, it is commonly required that such a
material be essentially sterile, e.g., for injectibles.
[0123] As used herein, the term "composition" refers to a
formulation suitable for administration to an intended animal
subject for therapeutic purposes; exemplary formulations contain at
least one pharmaceutically active compound and at least one
pharmaceutically acceptable carrier or excipient. Other terms as
used herein are defined below.
[0124] Adipocyte: An animal connective tissue cell specialized for
the synthesis and storage of fat.
[0125] Agonist: A chemical compound that has affinity for and
stimulates physiological activity at cell receptors normally
stimulated by naturally occurring substances, triggering a
biochemical response. An agonist of a receptor can also be
considered an activator of the receptor.
[0126] About: is used herein to mean in quantitative terms plus or
minus 10%.
[0127] Adipose tissue: Tissue comprised principally of
adipocytes.
[0128] Adolescent: A person between 10 and 19 years of age.
[0129] Adiponectin: A protein hormone produced and secreted
exclusively by adipocytes that regulates the metabolism of lipids
and glucose. Adiponectin influences the body's response to insulin.
Adiponectin also has anti-inflammatory effects on the cells lining
the walls of blood vessels.
[0130] Amelioration of the symptoms of a particular disorder by
administration of a particular pharmaceutical composition: refers
to any lessening, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the composition.
[0131] Analog: a compound that resembles another in structure but
differs by at least one atom.
[0132] Antagonist: A substance that tends to nullify the action of
another, as a drug that binds to a cell receptor without eliciting
a biological response.
[0133] Atherosclerotic Plaque: A buildup of cholesterol and fatty
material within a blood vessel due to the effects of
atherosclerosis
[0134] Bariatric Surgery: a range of surgical procedures which are
designed to aid in the management or treatment of obesity and
allied diseases.
[0135] Beta cell rest: Temporarily placing beta cells in a
condition in which there is reduced metabolic stress due to
suppressed secretion of insulin.
[0136] Bilaminate: A component of a pharmaceutical dosage form that
consists of the lamination of two distinct materials.
[0137] Bioavailability: Refers to the amount or extent of
therapeutically active substance that is released from the drug
product and becomes available in the body at the intended site of
drug action. The amount or extent of drug released can be
established by the pharmacokinetic-parameters, such as the area
under the blood or plasma drug concentration-time curve (AUC) and
the peak blood or plasma concentration (C max) of the drug.
[0138] Bioequivalent: Two formulations of the same active substance
are bioequivalent when there is no significant difference in the
rate and extent to which the active substance becomes available at
the site of drug action when administered at the same molar dose
under similar conditions. "Formulation" in this definition may
include the free base of the active substance or different salts of
the active substance. Bioequivalence may be demonstrated through
several in vivo and in vitro methods. These methods, in descending
order of preference, include pharmacokinetic, pharmacodynamic,
clinical and in vitro studies. In particular, bioequivalence is
demonstrated using pharmacokinetic measures such as the area under
the blood or plasma drug concentration-time curve (AUC) and the
peak blood or plasma concentration (Cmax) of the drug, using
statistical criteria.
[0139] Cannabinoid Receptor: Receptors in the endocannabinoid (EC)
system associated with the intake of food and tobacco dependency.
Blocking the cannabinoid receptor may reduce dependence on tobacco
and the craving for food.
[0140] Combination: refers to any association between or among two
or more items. The combination can be two or more separate items,
such as two compositions or two collections. It can be a mixture
thereof, such as a single mixture of the two or more items, or any
variation thereof.
[0141] Composition: refers to any mixture. It can be a solution, a
suspension, liquid, powder, a paste, aqueous, non-aqueous or any
combination thereof.
[0142] Compression tablet: Tablet formed by the exertion of
pressure to a volume of tablet matrix in a die.
[0143] Compression coated tablet: A tablet formed by the addition
of a coating by compression to a compressed core containing the
pharmaceutical active.
[0144] Derivative: a chemical substance derived from another
substance by modification or substitution.
[0145] Daily dosage: the total amount of a drug taken in a 24 hour
period whether taken as a single dose or taken in multiple
doses.
[0146] Diazoxide: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1
dioxide with the empirical formula C.sub.8H.sub.7ClN.sub.2O.sub.2S
and a molecular weight of 230.7.
[0147] Encapsulation system: a structural feature that contains
drug within such as a pharmaceutical capsule. A gel into which drug
is incorporated also is considered an encapsulation system.
[0148] Equivalent amount: an amount of a derivative of a drug that
in assays or upon administration to a subject produces an equal
effect to a defined amount of the non-derivatized drug.
[0149] Fatty acid synthase: The central enzyme of a multienzyme
complex that catalyses the formation of palmitate from
acetylcoenzyme A, malonylcoenzyme A, and NADPH.
[0150] Gastric Lipase: An enzyme secreted into the gastrointestinal
tract that catalyzes the hydrolysis of dietary triglycerides.
[0151] Glidant: An inactive component of a pharmaceutical
formulation that prevents caking of the matrix during processing
steps.
[0152] Growth hormone: also known as somatotropin or somatropin, is
a peptide hormone that stimulates growth, cell reproduction and
regeneration in humans and other animals. It is a type of mitogen
which is specific only to certain kinds of cells. Growth hormone is
a 191-amino acid, single-chain polypeptide that is synthesized,
stored, and secreted by somatotropic cells within the lateral wings
of the anterior pituitary gland. GH is a stress hormone that raises
the concentration of glucose and free fatty acids. It also
stimulates production of IGF-1.
[0153] Hyperinsulemia: Excessively high blood insulin levels, which
is differentiated from hyperinsulinism, excessive secretion of
insulin by the pancreatic islets. Hyperinsulinemia may be the
result of a variety of conditions, such as obesity and
pregnancy.
[0154] Hyperinsulinism: Excessive secretion of insulin by the
pancreatic islets.
[0155] Hyperlipidemia: A general term for elevated concentrations
of any or all of the lipids in the plasma, such as cholesterol,
triglycerides and lipoproteins.
[0156] Hyperphagia: Ingestion of a greater than optimal quantity of
food.
[0157] Ingredient of a pharmaceutical composition: refers to one or
more materials used in the manufacture of a pharmaceutical
composition. Ingredient can refer to an active ingredient (an
agent) or to other materials in the compositions. Ingredients can
include water and other solvents, salts, buffers, surfactants,
water, non-aqueous solvents, and flavorings.
[0158] IGF-1, also called somatomedin C, is a protein that in
humans is encoded by the IGF1 gene. IGF-1 is a hormone similar in
molecular structure to insulin. It plays an important role in
childhood growth and continues to have anabolic effects in adults.
IGF-1 consists of 70 amino acids in a single chain with three
intramolecular disulfide bridges, and has a molecular weight of
7,649 daltons.
[0159] Insulin resistance: A condition in which the tissues of the
body are diminished in their response to insulin.
[0160] Ischemic injury: injury to tissue that results from a low
oxygen state usually due to obstruction of the arterial blood
supply or inadequate blood flow leading to hypoxia in the
tissue.
[0161] Ketoacidosis: Acidosis accompanied by the accumulation of
ketone bodies (ketosis) in the body tissue and fluids, as in
diabetic acidosis.
[0162] Kit: refers to a packaged combination. A packaged
combination can optionally include a label or labels, instructions
and/or reagents for use with the combination.
[0163] Kir: Pore forming subunit of the K.sub.ATP channel. Also
known as the inwardly rectifying subunit of the K.sub.ATP channel.
Typically existing as Kir6.x and infrequently as Kir2.x
subspecies.
[0164] K.sub.ATP channel: An ATP sensitive potassium ion channel
across the cell membrane formed by the association of 4 copies of a
sulfonylurea receptor and 4 copies of a pore forming subunit Kir.
Agonizing the channel can lead to membrane hyperpolarization.
[0165] Lean body mass: Lean Body Mass is a component of body
composition, calculated by subtracting body fat weight from total
body weight: total body weight is lean plus fat. In equations:
Lean Body Mass equals Body Weight minus Body Fat (LBM=BW-BF)
Lean Body Mass plus Body Fat equals Body Weight (LBM+BF=BW)
The percentage of total body mass that is lean is usually not
quoted--it would typically be 60-90%. Instead, the body fat
percentage, which is the complement, is computed, and is typically
10-40%. The Lean body mass (LBM) has been described as an index
superior to total body weight for prescribing proper levels of
medications and for assessing metabolic disorders, as body fat is
less relevant for metabolism.
[0166] Leptin: Product (16 kD) of the ob (obesity) locus. It is
found in plasma of mammals and exerts a hormonal action, which
reduces food uptake and increases energy expenditure.
[0167] Lipogenesis: The generation of new lipids, primarily
triacylglycerides. It is dependent on the action of multiple
distinct enzymes and transport molecules.
[0168] Lipolysis: The breakdown of fat by the coordinated action of
multiple enzymes.
[0169] Lipoprotein lipase: An enzyme of the hydrolase class that
catalyses the reaction of triacyglycerol and water to yield
diacylglyerol and a fatty acid anion. The enzyme hydrolyses
triacylglycerols in chylomicrons, very-low-density lipoproteins,
low-density lipoproteins, and diacylglycerols.
[0170] Lubricant: An inactive component of a pharmaceutical
formulation that provides for the flow of materials in various
processing steps, particularly tableting.
[0171] Microparticle: A small particulate formed in the process of
developing pharmaceutical formulations that may be coated prior to
producing the final dosage from.
[0172] Obesity: An increase in body weight beyond the limitation of
skeletal and physical requirement, as the result of an excessive
accumulation of fat in the body. Formally defined as having a body
mass index greater than 30 kg/m.sup.2.
[0173] Obesity Prone: Individuals who because of genetic
predisposition or prior history of obesity are at above average
risk of becoming obese.
[0174] Obesity related co-morbidities: any disease or condition of
animals or humans that are increased incidence in obese or
overweight individuals. Examples of such conditions include
hypertension, prediabetes, type 2 diabetes, osteoarthritis and
cardiovascular conditions.
[0175] Osmotically controlled release: A pharmaceutical dosage form
in which the release of the active drug is principally achieved by
the hydration of a swellable component of the formulation.
[0176] Overweight: an individual whose weight is above that which
is ideal for their height but who fails to meet the criteria for
classification as obese. In humans using Body Mass Index
(kg/m.sup.2) an overweight individual has a BMI between 25 and
30.
[0177] Oxidation of Fat: A series of reactions involving
acyl-coenzyme A compounds, whereby these undergo beta oxidation and
thioclastic cleavage, with the formation of acetyl-coenzyme A; the
major pathway of fatty acid catabolism in living tissue.
[0178] Pharmaceutical composition: refers a composition that
contains an agent and one or more other ingredients that is
formulated for administration to a subject. An agent refers to an
active ingredient of a pharmaceutical composition. Typically active
ingredients are active for treatment of a disease or condition. For
example, agents that can be included in pharmaceutical compositions
include agents for treating obesity or diabetes. The
pharmaceutically active agent can be referred to as "a
pharmaceutical active."
[0179] Pharmaceutical effect: refers to an effect observed upon
administration of an agent intended for treatment of a disease or
disorder or for amelioration of the symptoms thereof.
[0180] Pharmacodynamic: An effect mediated by drug action.
[0181] Pharmacokinetic: Relating to the absorption, distribution,
metabolism and elimination of the drug in the body.
[0182] Polymorph: A compound that shares the same chemistry but a
different crystal structure.
[0183] Prader-Milli syndrome (PWS): A complex
neurobehavioral/metabolic disorder which is due to the absence of
normally active, paternally expressed genes from the chromosome
15q11-q13 region. PWS is an imprinted condition with 70-75% of the
cases due to a de novo deletion in the paternally inherited
chromosome 15 11-q13 region, 20-30% from maternal uniparental
disomy 15 (UPD), and the remaining 2-5% from either microdeletions
or epimutations of the imprinting center (i.e., imprinting defects)
(Bittel and Butler, Expert Rev Mol Med 7(14):1-20 (2005); Cassidy
and Driscoll, Eur J Hum Genet 17(1):3-13(2009)).
[0184] The clinical manifestations of the condition begin in utero
with diminished fetal activity (Miller Am J Med Genet A
155A(5):1-10 (2011)). Low lean body mass and hypotonia are
universal in PWS and present throughout life (Brambilla Am J Clin
Nutr 65(5):1369-1374 (1997), Lloret-lineras Int J Obes 37:1198-1203
(2013)). Mental retardation occurs to varying degrees with the
average IQ being 70 (PWSUSA). PWS patients present with a range of
behavioral complications including autistic-spectrum-disorder-like
behaviors, compulsive behaviors, self-injurious behaviors, and
aggressive, threatening and destructive behaviors. About 80% of PWS
patients are growth hormone deficient (Goldstone, Trends Endocrinol
Metab 15:12-120 (2004); Davies et al., Front Neuroendocrinol
29:413-427 (2008); Cassidy and Driscoll, 2009, supra). Nearly all
PWS patients are hypogonadal, requiring sex hormone supplementation
(Goldstone, 2004, supra; Davies et al., 2008, supra; Cassidy and
Driscoll, 2009, supra). These patients have hypothalamic
insufficiency/dysfunction (Goldstone Am J Clin Nutr 75(3):468-475
(2002)).
[0185] The accumulation of excess body fat may begin about age 2
and can continue into adulthood (Miller 2011, supra). The vast
majority of body fat in PWS is subcutaneous (Brambilla 1997, supra;
Sode-Carlson, Growth hormone and IGF research 20:179-184 (2010),
Bedogni J Endocrinol Invest DOI 10.1007/s40618-015-0266-y (2015)).
Obesity is not universal in PWS, unlike the universality of low
lean body mass and hypotonia. For example, Sode-Carlson et al.
(2010), supra, evaluated 46 adult PWS patients, 25 women and 21
men. The average BMI in these adult PWS patients was 27.2
kg/m.sup.2. Thus, on average, these patients were overweight rather
than obese, suggesting that more than half are not, in fact, obese
by the best metric. Similarly, Brambilla et al. Nutr Metab
Cardiovasc Dis 21(4):269-276 (2011) studied a population of 109
children with PWS. They found that 54% were not classified as obese
by the best metric. Thus, both in adults and in children with PWS,
obesity is not only not universal, but may, in fact, occur in less
than half of the population. Subcutaneous fat makes up a greater
percentage of total fat in PWS than it does in obese controls at
all ages (Sode-Carlson 2010, supra).
[0186] Hyperphagia with the associated problematic food related
behaviors begins on average about age 8 (Miller 2011, supra). These
patients sense they are starving when they are not. Upon the onset
of hyperphagia, PWS patients will eat any food in the line of
sight, get up at night to eat, dig through the trash for food,
steal food, consume frozen food, pet food, spoiled food and even
consume non-food items (Miller 2011, supra). They will become angry
or throw tantrums if denied food. At this stage and thereafter
throughout life, access to food is strictly limited, with cabinets
and refrigerators being locked. To limit food related anxiety, meal
times and meal composition are strictly regimented.
[0187] The mortality rate for PWS patients is three times that of
the general population at all ages (Cassidy Genet Med 14(1):10-26
(2012)), with the average age at death being about 29 years (PWSUSA
mortality database, n=488). In contrast, being obese, but not
morbidly obese has little impact on life expectancy (Anon (2011)
National Research Council Panel on Understanding Divergent Trends
in Longevity in High-Income Countries; Crimmons, E M, Preston, SH,
Cohen, B, editors. National Academies Press).
[0188] Prader-Willi patients expend less energy and are more
sedentary than either the general population, obese controls or
patients with similar intellectual disabilities. Butler et al. Am J
Med Gent A 143A(5):449-459 (2007)) compared the energy expenditure
and total work of a group of 48 PWS patients with a group of 24
obese controls. Compared to the controls, PWS patients had
significantly decreased total energy expenditure (-20%), resting
energy expenditure (-16%) and mechanical work (-35%). After
adjusting for group differences in lean body mass, the difference
remained significant for mechanical work.
[0189] In a study by van Mil et al., Int J Obes Relat Metab Disord
24(4):429-434 (2000), the authors measured basal metabolic rate
(BMR), average daily metabolic rate (ADMR), activity induced energy
expenditure (AEE), and ADMR/BMR (PAL) in a group of PWS patients
and matched controls. ADMR, AEE and PAL were significantly lower
(P<0.01) in the PWS group compared with the control group
-28.2%, -58.2%, and -14.2%, respectively).
[0190] De Lind van Wijngaarden et al, J Clin Endocrinol Metab
95(4):1758-1766 (2010) evaluated cardiovascular and metabolic risk
factors in children with PWS. They showed that 63% of infants and
73% of pre-pubertal children with PWS have at least one
cardiovascular risk factor, defined as dyslipidemia or
hypertension. Thus, the cardiometabolic risk in PWS is elevated
even in younger children.
[0191] Preadipocyte: A progenitor cell to adipocytes.
[0192] Prediabetic: A condition that precedes diagnosis of type II
diabetes. Type II diabetes is a form of diabetes mellitus which is
characterized by insulin insensitivity or resistance.
[0193] Prodrug: refers to a compound which, when metabolized,
yields the desired active compound. Typically, the prodrug is
inactive, or less active than the active compound, but may provide
advantageous handling, administration, or metabolic properties. For
example, some prodrugs are esters of the active compound; during
metabolysis, the ester group is cleaved to yield the active drug.
Also, some prodrugs are activated enzymatically to yield the active
compound, or a compound which, upon further chemical reaction,
yields the active compound.
[0194] Prolonged Administration (prolonged basis): Administration
of a pharmaceutically acceptable formulation of a drug for 7 or
more days. Typically, prolonged administration is for at least two
weeks, preferably at least one month, and even more preferably at
least two months (i.e. at least 8 weeks).
[0195] Quick dissolving formulation: a pharmaceutical formulation
which upon oral administration may release substantially all of the
drug active from the formulation within 10 minutes.
[0196] Release formulation (sustained), (or "sustained release
formulation"): A formulation of pharmaceutical product that, upon
administration to animals, provides for release of the active
pharmaceutical over an extended period of time than provided by
formulations of the same pharmaceutical active that result in rapid
uptake. Similar terms are extended-release, prolonged-release, and
slow-release. In all cases, the preparation, by definition, has a
reduced rate of release of active substance.
[0197] Release formulation (delayed), (or "delayed release
formulation"): Delayed-release products are modified-release, but
are not extended-release. They involve the release of discrete
amount(s) of drug some time after drug administration, e.g.
enteric-coated products, and exhibit a lag time during which little
or no absorption occurs.
[0198] Release formulation (controlled), (or "controlled release
formulation"): A formulation of pharmaceutical product that may
include both delay of release of pharmaceutical active upon
administration and control of release in the manner described for
sustained release.
[0199] Salt: the neutral, basic or acid compound formed by the
union of an acid or an acid radical and a base or basic
radical.
[0200] Smith-Magenis syndrome (SMS; OMIM #182290, *607642): A
complex, generally sporadic, genetic disorder caused by
haploinsufficiency of the retinoic acid induced 1 (RAI1) gene.
caused by either a 17p11.2 deletion encompassing the retinoic
acid-induced 1 (RAI1) gene or a mutation of RAI1. (see, for
example, Burns et al., in Human Molecular Genetics, 2010, Vol. 19,
No. 20, pp. 4026-4042).
[0201] Smith-Magenis syndrome is characterized by a clinically
recognizable phenotype that includes physical, developmental,
neurological, and behavioral features. Short stature (<5th
percentile) was observed in .about.67% of young patients. Short
stature resolves over time with most individuals reaching the
10-25th percentile by adulthood (see, for example, Burns et al.
supra). A majority of children with SMS also have significant
early-onset obesity (see, for example, European Journal of Human
Genetics (2008) 16, 412-421). Obesity in teens and adults is
common, typically with broad chests and truncal obesity. RAD
haploinsufficiency represents a single-gene model of obesity with
hyperphagia, abnormal fat distribution and altered hypothalamic
gene expression associated with satiety, food intake, behavior and
obesity.
[0202] Hearing loss is variable and is often associated with
chronic ear infections. Ophthalmologic features are present in
>60% of SMS patients and include myopia, iris anomalies,
strabismus, microcornea, and, rarely, retinal detachment (often
resulting from violent behaviors).
[0203] Prenatal history of SMS is notable for significantly
decreased fetal movement in 50% of pregnancies. Early infancy is
complicated by feeding difficulties leading to failure to thrive,
marked oral sensory motor dysfunction with poor suckling reflex,
gastroesophageal reflux, and hypotonia.
[0204] Most SMS individuals have mild-to-moderate mental
retardation. IQ decreases as the child ages, ultimately placing the
individual in the mild mental retardation range by adulthood.
Delayed speech with or without hearing loss occurs in 96% of SMS
patients. In addition, delayed fine/gross motor skills, problems
with sensory integration, and poor adaptive function are seen.
Other neurological features include pes cavus or pes planus, an
abnormal `festinating` gait, balance problems, and a decreased
sensitivity to pain, which is often observed in association with
self-injury in this disorder.
[0205] Sleep disturbance has been reported in 75-100% of SMS cases.
Infants typically experience hypersomnolence during the first year
of life. Sleep disturbances in older children include difficulties
falling asleep, diminished REM sleep, reduced 24-h and night sleep,
fragmented and shortened sleep cycles with frequent nocturnal and
early-morning awakenings, and excessive daytime sleepiness.
[0206] Behavioral issues are one of the unique characteristic
features of SMS. Maladaptive behaviors are a cause of major concern
and include frequent outbursts/temper tantrums, attention seeking,
aggression, disobedience, distraction, and self-injurious
behaviors. Self-injurious behaviors include head banging, skin
picking, wrist biting, onychotillomania and polyembolokoilamania.
The behavioral phenotype of SMS escalates with age, typically with
the onset of puberty. Age, degree of developmental delay, severity
of any associated systemic disorder, and degree of sleep
disturbance have a strong influence on maladaptive behaviors.
Individuals also have a lack of respect for personal space during a
conversation and are emotionally volatile.
[0207] SMS patients share many characteristics in common with PWS
patients. These include: (1) diminished fetal activity; (2)
hypotonia; (3) feeding difficulties in early infancy; (4) short
stature: (5) early onset obesity which may include hyperphagia; (6)
developmental delays; (7) mental retardation; (8) temper outbursts;
(9) aggressive behavior; (10) self-injurious behavior; (11)
hypersomnolence in infancy and similar sleep disturbances in older
children and adults; (12) frequent ear infections; (13) scoliosis;
and (14) strabismus. While the underlying genetic basis for these
disorders is quite distinct, the presentation and natural history
of the disease is very similar.
[0208] Solid oral dosage form: pharmaceutical formulations designed
for oral administration including capsules and tablets.
[0209] Subject: refers to animals, including mammals, such as human
beings.
[0210] Sulfonylurea receptor: A component of the K.sub.ATP channel
responsible for interaction with sulfonylurea, other K.sub.ATP
channel antagonists, diazoxide and other K.sub.ATP channel
agonists.
[0211] Tablet: Pharmaceutical dosage form that is produced by
forming a volume of a matrix containing pharmaceutical active and
excipients into a size and shape suitable for oral
administration.
[0212] Thermogenesis: The physiological process of heat production
in the body.
[0213] Threshold Concentration: The minimum circulating
concentration of a drug required to exert a specific metabolic,
physiological or compositional change in the body of a treated
human or animal.
[0214] Treatment: means any manner in which the symptoms of a
condition, disorder or disease or other indication, are ameliorated
or otherwise beneficially altered.
[0215] Triglyceride: Storage fats of animal and human adipose
tissue principally consisting of glycerol esters of saturated fatty
acids.
[0216] Type I diabetes: A chronic condition in which the pancreas
makes little or no insulin because the beta cells have been
destroyed.
[0217] Uncoupling protein: A family of proteins that allow
oxidation in mitochondria to proceed without the usual concomitant
phosphorylation to produce ATP.
[0218] Visceral fat: Human adipose tissues principally found below
the subcutaneous fat and muscle layer in the body.
BRIEF DESCRIPTION OF THE FIGURES
[0219] FIG. 1 summarizes the change in hyperphagia score for all
subjects who participated in clinical study PC025.
[0220] FIG. 2 summarizes the percent change in lean body mass for
all subjects who participated in clinical study PC025.
[0221] FIG. 3 summarizes the percent change in body fat mass for
all subjects who participated in clinical study PC025.
[0222] FIG. 4 summarizes the percent change of the lean body
mass/fat mass ratio for all subjects who participated in clinical
study PC025.
[0223] FIG. 5 summarizes the clinical study treatment schedule for
pediatric and adult patients who have PWS and are obese.
DETAILED DESCRIPTION OF THE INVENTION
[0224] Provided herein are pharmaceutical formulations of
particular K.sub.ATP channel openers that when administered to
subjects achieve novel pharmacodynamic, pharmacokinetic,
therapeutic, physiological, and metabolic outcomes. Also provided
are pharmaceutical formulations, methods of administration and
dosing of particular K.sub.ATP channel openers, optionally in
combination with growth hormone, that achieve therapeutic outcomes
while reducing the incidence of adverse effects.
[0225] In particular, pharmaceutical formulations formulated for
oral administration exhibit advantageous properties including:
facilitating consistency of absorption, pharmacokinetic and
pharmacodynamic responses across treated patients, contributing to
patient compliance and improving the safety profile of the product,
such as by reducing the frequency of serious adverse effects.
Method of treatment of metabolic and other diseases of humans and
animals by administering the formulations are also provided.
[0226] Compounds of formulas II and III, formulas IV and V, and
formulas VI and VII, such as for example, diazoxide (shown below)
can be proton tautomers. Proton tautomers are isomers that differ
from each other only in the location of a hydrogen atom and a
double bond. The hydrogen atom and double bond switch locations
between a carbon atom and a heteroatom, such as for example N.
Thus, when the nitrogen substituent is hydrogen, the two isomeric
chemical structures may be used interchangeably.
##STR00008##
[0227] The particular K.sub.ATP channel openers that can be used in
the invention formulations include any of those within formulae I
to VII. Exemplary such compounds include diazoxide, BPDZ62, BPDZ
73, NN414 and BPDZ 154 (see, for example, Schou, et al., Bioorg.
Med. Chem., 13, 141-155 (2005)). Compound BPDZ 154 also is an
effective K.sub.ATP channel activator in patients with
hyperinsulinism and in patients with pancreatic insulinoma. The
synthesis of BPDZ compound is provided in Cosgrove, et al., J.
Clin. Endocrinol. Metab., 87, 4860-4868 (2002).
[0228] Analogs of diazoxide include
3-isopropylamino-7-methoxy-4H-1,2,4,-benzothiadiazine 1,1-dioxide,
which is a selective Kir6.2/SUR1 channel opener (see Dabrowski, et
al., Diabetes, 51, 1896-1906 (2002)). 2-alkyl substituted
diazoxides are included (see, for example, Ouedraogo, et al., Biol.
Chem., 383, 1759-1768 (2002)); these channel openers show decreased
activity in the inhibition of insulin release and increased
activity in vascular smooth muscle tissue. Furthermore, 2-alkyl
substituted diazoxides generally do not function as traditional
potassium channel activators, but instead show potential as
Ca.sup.2+ blockers.
[0229] Other diazoxide analogs are described in Schou, et al.,
Bioorg. Med. Chem., 13, 141-155 (2005), and are shown below.
##STR00009##
[0230] Diazoxide analogs having different alkyl substituents at the
3 position of the molecule (identified as R.sup.3 shown below) are
described in Bertolino, et al., Receptors and Channels, 1, 267-278
(1993).
##STR00010##
[0231] K.sub.ATP channel activity of formulae I-VII and related
compounds can be measured by membrane potential studies as
described in Schou, et al., Bioorg. Med. Chem., 13, 141-155 (2005)
and Dabrowski, et al., Diabetes, 51, 1896-1906 (2002).
[0232] Measurement of the inhibition of glucose-stimulated insulin
release from .beta.TC6 cells is described in Schou, et al., Bioorg.
Med. Chem., 13, 141-155 (2005). The ability of particular K.sub.ATP
channel openers to inhibit release of insulin from incubated rat
pancreatic islets can be performed as described by Ouedraogo, et
al., Biol. Chem., 383, 1759-1768 (2002).
[0233] Activation of recombinant K.sub.ATP channels by K.sub.ATP
channel openers can be examined by monitoring macroscopic currents
of inside-out membrane patches from Xenopus oocytes coexpressing
Kir6.2 and either SUR1, SUR2A or SUR2B. SUR expressing membranes
can be prepared by known methods. See, for example, Dabrowski, et
al., Diabetes, 51, 1896-1906 (2002).
[0234] Binding experiments can be used to determine the ability of
K.sub.ATP channel openers to bind SUR1, SUR2A and SUR2B. See, for
example, Schwanstecher, et al., EMBO 1, 17, 5529-5535 (1998).
[0235] Preparation of SUR1 and SUR2A chimeras, as described by
Babenko et al., allows for comparison of pharmacologic profiles
(i.e. sulfonyl sensitivity and responsiveness to diazoxide or other
potassium channel openers) of the SUR1/Kir6.2 and SUR2A/Kir6.2
potassium channels. See Babenko, et al., J. Biol. Chem., 275(2),
717-720 (2000). The cloning of a sulfonylurea receptor and an
inwardly rectifying K.sup.+ channel is described by Isomoto, et
al., J. Biol. Chem., 271 (40), 24321-24324 (1996); D'hahan, et al.,
PNAS, 96(21), 12162-12167 (1999).
[0236] Differences between the human SUR1 and human SUR2 genes are
described and shown in Aguilar-Bryan, et al., Physiological Review,
78(1), 227-245 (1998).
[0237] "Halo" and "halogen" refer to all halogens, that is, chloro
(Cl), fluoro (F), bromo (Br), or iodo (I).
[0238] "Hydroxyl" and "hydroxy" refer to the group --OH.
[0239] "Substituted oxy" refers to the group --OR.sup.f, where
R.sup.f is alkyl, substituted alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,
cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted
heterocyclyl.
[0240] "Substituted thiol" refers to the group --SR, where R is
alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted
aralkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or
substituted heterocyclyl.
[0241] "Alkyl" refers to an alkane-derived radical containing from
1 to 10, preferably 1 to 6, carbon atoms. Alkyl includes straight
chain alkyl, branched alkyl and cycloalkyl, such as methyl, ethyl,
propyl, isopropyl, butyl, t-butyl, and the like. Straight chain or
branched alkyl groups contain from 1-10, preferably 1 to 6, more
preferably 1-4, yet more preferably 1-2, carbon atoms. The alkyl
group is attached at any available point to produce a stable
compound.
[0242] A "substituted alkyl" is an alkyl group independently
substituted with 1 or more, e.g., 1, 2, or 3, groups or
substituents such as halo, hydroxy, optionally substituted alkoxy,
optionally substituted alkylthio, alkylsulfinyl, alkylsulfonyl,
optionally substituted amino, optionally substituted amido,
amidino, urea optionally substituted with alkyl, aminosulfonyl
optionally N-mono- or N,N-di-substituted with alkyl,
alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,
nitro, cyano, thiol, sulfonylamino or the like attached at any
available point to produce a stable compound. In particular, "fluro
substituted" refers to substitution by 1 or more, e.g., 1, 2, or 3
fluorine atoms. "Optionally fluro substituted" means that
substitution, if present, is fluoro.
[0243] "Lower alkyl" refers to an alkyl group having 1-6 carbon
atoms.
[0244] A "substituted lower alkyl" is a lower alkyl which is
substituted with 1 or more, e.g., 1, 2, or 3, groups or
substituents as defined above, attached at any available point to
produce a stable compound.
[0245] "Cycloalkyl" refers to saturated or unsaturated,
non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems
of 3-8, more preferably 3-6, ring members per ring, such as
cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
"Cycloalkylene" is a divalent cycloalkyl.
[0246] "Alkoxy" denotes the group --OR.sup.f, where R.sup.f is
lower alkyl.
[0247] "Substituted alkoxy" denotes the group --OR.sup.f', where
R.sup.f' is substituted lower alkyl.
[0248] "Alkylthio" or "thioalkoxy" refers to the group --S--R,
where R is lower alkyl.
[0249] "Substituted alkylthio" or "substituted thioalkoxy" refers
to the group --S--R, where R is substituted lower alkyl.
[0250] "Sulfinyl" denotes the group --S(O)--.
[0251] "Sulfonyl" denotes the group --S(O).sub.2--.
[0252] "Substituted sulfinyl" denotes the group --S(O)--R, where R
is lower alkyl, substituted lower alkyl, cycloalkyl, substituted
cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl,
heterocyclyl, substituted heterocyclyl, heterocyclylalkyl,
substituted hetereocyclylalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,
aralkyl or substituted aralkyl.
[0253] "Substituted sulfonyl" denotes the group --S(O).sub.2--R,
where R is lower alkyl, substituted lower alkyl, cycloalkyl,
substituted cycloalkyl, cycloalkylalkyl, substituted
cycloalkylalkyl, heterocyclyl, substituted heterocyclyl,
heterocyclylalkyl, substituted hetereocyclylalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl,
heteroaralkyl, substituted heteroaralkyl, aralkyl or substituted
aralkyl.
[0254] "Sulfonylamino" denotes the group --NRS(O).sub.2-- where R
is hydrogen or lower alkyl.
[0255] "Substituted sulfonylamino" denotes the group
--NR.sup.aS(O).sub.2--R.sup.b, where R.sup.a is hydrogen or lower
alkyl and R.sup.b is lower alkyl, substituted lower alkyl,
cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted
heterocyclyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heteroaralkyl, substituted heteroaralkyl, aralkyl or
substituted aralkyl.
[0256] "Amino" or "amine" denotes the group --NH.sub.2. A "divalent
amine" denotes the group --NH--. A "substituted divalent amine"
denotes the group --NR-- wherein R is lower alkyl, substituted
lower alkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, acyl, substituted acyl, sulfonyl or substituted
sulfonyl.
[0257] "Substituted amino" or "substituted amine" denotes the group
wherein R' and R.sup.j are independently hydrogen, lower alkyl,
substituted lower alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, acyl, substituted acyl, sulfonyl,
substituted sulfonyl, or cycloalkyl provided, however, that at
least one of R.sup.i and R.sup.j is not hydrogen. R.sup.iR.sup.j in
combination with the nitrogen may form an optionally substituted
heterocyclic or heteroaryl ring.
[0258] "Alkylsulfinyl" denotes the group --S(O)R.sup.p, wherein
R.sup.p is optionally substituted alkyl.
[0259] "Alkylsulfonyl" denotes the group --S(O).sub.2R.sup.p,
wherein R.sup.p is optionally substituted alkyl.
[0260] "Alkylsulfonylamino" denotes the group
--NR.sup.qS(O).sub.2R.sup.p, wherein R.sup.p is optionally
substituted alkyl, and R.sup.q is hydrogen or lower alkyl.
[0261] Pharmaceutical formulations containing K.sub.ATP channel
openers include the free base of the drug or a salt of the drug.
Such salts may have one or more of the following characteristics:
(1) stability in solution during synthesis and formulation, (2)
stability in a solid state, (3) compatibility with excipients used
in the manufacture of tablet formulations, (4) quantitatively yield
the K.sub.ATP channel opener upon exposure to simulated or actual
gastric and duodenal conditions, (5) release K.sub.ATP channel
opener from sufficiently small particles that are readily dissolved
and absorbed, (6) provide, when incorporated into a pharmaceutical
formulation, for absorption of greater than 80% of the administered
dose, (7) present no elevated toxicological risk as compared to the
free base of the K.sub.ATP channel opener, (8) can be formulated
into acceptable pharmaceutical formulations to treat obesity and
other diseases of humans, (9) are acceptable to the FDA as the
basis of a drug product, (10) can be recrystallized to improve
purity, (11) can be used to form co-crystals of two or more salts
of the K.sub.ATP channel opener, (12) have limited hygroscopicity
to improve stability, or (13) synthetic and crystallization
conditions under which the salt is formed can be varied resulting
in different crystal structures (polymorphs) can be controlled in
the synthesis of the salt.
[0262] K.sub.ATP channel openers can be formulated as
pharmaceutically acceptable salts. Pharmaceutically acceptable
salts are non-toxic salts in the amounts and concentrations at
which they are administered. The preparation of such salts can
facilitate the pharmacological use by altering the physical
characteristics of a compound without preventing it from exerting
its physiological effect. Useful alterations in physical properties
include lowering the melting point to facilitate transmucosal
administration and increasing the solubility to facilitate
administering lower effective doses of the drug.
[0263] Pharmaceutically acceptable salts include acid addition
salts such as those containing sulfate, chloride, hydrochloride,
fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate,
tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, cyclohexylsulfamate and quinate.
Pharmaceutically acceptable salts can be obtained from acids such
as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid,
sulfamic acid, acetic acid, citric acid, lactic acid, tartaric
acid, malonic acid, methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic
acid, fumaric acid, and quinic acid.
[0264] Pharmaceutically acceptable salts also include basic
addition salts such as those containing benzathine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine, procaine,
aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium,
alkylamine, and zinc, when acidic functional groups, such as
carboxylic acid or phenol are present. For example, see Remington's
Pharmaceutical Sciences, 19.sup.th ed., Mack Publishing Co.,
Easton, Pa., Vol. 2, p. 1457, 1995. Such salts can be prepared
using the appropriate corresponding bases.
[0265] Pharmaceutically acceptable salts can be prepared, for
example, by dissolving the free-base form of a compound in a
suitable solvent, such as an aqueous or aqueous-alcohol in solution
containing the appropriate acid and then isolated by evaporating
the solution. In another example, a salt is prepared by reacting
the free base and acid in an organic solvent.
[0266] The pharmaceutically acceptable salt of the different
compounds may be present as a complex. Examples of complexes
include 8-chlorotheophylline complex (analogous to, e.g.,
dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex;
Dramamine) and various cyclodextrin inclusion complexes.
[0267] Salts of K.sub.ATP channel openers, and particular salts of
diazoxide, may include, but are not limited to acetate, acetonide,
acetyl, adipate, aspartate, besylate, biacetate, bitartrate,
bromide, butoxide, butyrate, calcium, camsylate, caproate,
carbonate, citrate, cyprionate, decaroate, diacetate, dimegulumine,
dinitrate, dipotassium, dipropionate, disodium, disulfide,
edisylate, enanthate, estolate, etabonate, ethylsuccinate,
fumarate, furoate, gluceptate, gluconate, hexacetonide, hippurate,
hyclate, hydrobromide, hydrochloride, isethionate, lactobionate,
malate, maleate, meglumine, methylbromide, methylsulfate,
metrizoate, nafate, napsylate, nitrate, oleate, palmitate, pamoate,
phenpropionate, phosphate, pivalate, polistirex, polygalacturonate,
probutate, propionate, saccharate, sodium glycinate, sodium
phosphate, podium succinate, state, succinate, sulfate, sulfonate,
sulfosalicylate, tartrate, tebutate, terephalate, terephthalate,
tosylate, triflutate, trihydrate, trisilicate, tromethamine,
valerate, xinafolate, or the like.
[0268] Formulations provided herein exhibit some or all the
following characteristics: (1) they are stable at ambient
temperatures for a minimum of one year; (2) they provide for ease
of oral administration; (3) they facilitate patient compliance with
dosing; (4) upon administration, they consistently facilitate high
levels of absorption of the pharmaceutical active; (5) upon once or
twice daily oral administration they allow release of the K.sub.ATP
channel opener over a sustained time frame such that the
circulating concentration of the K.sub.ATP channel opener or its
metabolically active metabolites does not fall below a
therapeutically effective concentration; (6) they achieve these
results independent of the pH of the gastrointestinal tract of
treated individuals, and (7) they delay release until gastric
transit is complete or nearly complete.
[0269] Formulations designed for oral administration can be
provided, for example, as capsules or tablets. Capsule or tablet
formulations include a number of distinguishing components. One is
a component to improve absorption of the K.sub.ATP channel opener.
Another sustains release of the drug over more than 2 hours. A
third delays substantial release of the drug until gastric transit
is completed.
[0270] The formulations disclosed herein exhibit improved
solubility and absorption of the K.sub.ATP channel opener compared
to previous formulations of these drugs. These advantageous
properties are achieved by any one or more of the following
approaches: (1) reducing particle size of the formulation by
comminution, spray drying, or other micronising techniques, (2)
using a pharmaceutical salt of the K.sub.ATP channel opener, (3)
using an ion exchange resin in the formulation, (4) using inclusion
complexes, for example using a cyclodextrin, (5) compaction of the
K.sub.ATP channel opener with a solubilizing agent including low
viscosity hypromellose, low viscosity metylcellulose or similarly
functioning excipient and combinations thereof, (6) associating the
K.sub.ATP channel opener with a salt prior to formulation, (7)
using a solid dispersion of the K.sub.ATP channel opener, (8) using
a self emulsifying system, (9) adding one or more surfactants to
the formulation, (10) using nanoparticles in the formulation, or
(11) combinations of these approaches. Preferably, when the
K.sub.ATP channel opener is a salt of diazoxide, the salt is not a
sodium salt.
[0271] Release of K.sub.ATP channel opener over a sustained period
of time (2-24 hours) is achieved by the use of one or more
approaches including, but not limited to: (1) the use of pH
sensitive polymeric coatings, (2) the use of a hydrogel, (3) the
use of a film coating that controls the rate of diffusion of the
drug from a coated matrix, (4) the use of an erodable matrix that
controls rate of drug release, (5) the use of polymer coated
pellets, granules, or microparticles which can be further
encapsulated or compressed into a tablet, (6) the use of an osmotic
pump system, or (7) the use of a compression coated tablet, or (8)
combinations of these approaches.
[0272] Delay of release of K.sub.ATP channel openers from the
formulation until gastric transit is complete is achieved in the
formulations provided herein by any of several mechanisms. A pH
sensitive polymer or co-polymer is used which when applied around
the drug matrix functions as an effective barrier to release of
active at pH 3.0 or lower and is unstable at pH 5.5 and above. This
provides for control of release of the active compound in the
stomach but rapidly allows release once the dosage form has passed
into the small intestine. An alternative to a pH sensitive polymer
or co-polymer is a polymer or co-polymer that is
non-aqueous-soluble. The extent of resistance to release in the
gastric environment can be controlled by coating with a blend of
the non-aqueous-soluble and a aqueous soluble polymer. In this
approach neither of the blended polymers or co-polymers are pH
sensitive. One example of a pH sensitive co-polymer is the Eudragit
methacrylic co-polymers, including Eudragit L100, 5100 or L100-55
solids, L30 D-55 or FS 30D dispersions, or the L12.5 or S12.5
organic solutions.
[0273] Polymers that delay release can be applied to a tablet
either by spray coating (as a thin film) or by compression coating.
If a capsule is used, then the polymer(s) may be applied over the
surface of the capsule or applied to microparticles of the drug,
which may then be encapsulated such as in a capsule or gel. If the
capsule is coated, then it will resist disintegration until after
gastric transit. If microparticles are coated, then the capsule may
disintegrate in the stomach but little to no drug will be released
until after the free microparticles complete gastric transit.
Finally, an osmotic pump system that uses e.g., a swellable
hydrogel can be used to delay drug release in the stomach. The
swellable hydrogel takes up moisture after administration. Swelling
of the gel results in displacement of the drug from the system for
absorption. The timing and rate of release of the drug depend on
the gel used, and the rate at which moisture reaches the gel, which
can be controlled by the size of the opening in the system through
which fluid enters. See Drug Delivery Technologies online article
Dong et al. "L-OROS.RTM. SOFTCAP.TM. for Controlled Release of
Non-Aqueous Liquid Formulations."
[0274] Accordingly, delay of release of K.sub.ATP channel openers
from the invention formulations until after gastric transit is
complete is achieved in the formulations provided herein by any of
several mechanisms, including, but not limited to: (a) a pH
sensitive polymer or co-polymer applied as a compression coating on
a tablet; (b) a pH sensitive polymer or co-polymer applied as a
thin film on a tablet; (c) a pH sensitive polymer or co-polymer
applied as a thin film to an encapsulation system; (d) a pH
sensitive polymer or co-polymer applied to encapsulated
microparticles, (e) a non-aqueous-soluble polymer or co-polymer
applied as a compression coating on a tablet; (f) a
non-aqueous-soluble polymer or co-polymer applied as a thin film on
a tablet; (g) a non-aqueous soluble polymer applied as a thin film
to an encapsulation system; (h) a non-aqueous soluble polymer
applied to microparticles; (i) incorporation of the formulation in
an osmotic pump system, or (j) use of systems controlled by ion
exchange resins, or (k) combinations of these approaches, wherein
the pH sensitive polymeror co-polymer is resistant to degradation
under acid conditions.
[0275] Formulations are provided that are designed for
administration once daily (per 24 hours). These can contain between
25 and 500 mg of K.sub.ATP channel openers. Formulations intended
for administration twice daily (per 24 hours) are also provided.
These can contain between 25 and 250 mg of K.sub.ATP channel
openers.
[0276] The formulations provided herein exhibit improved safety of
the administered drug product. This improvement in safety occurs by
at least two mechanisms. First, delay of release of active drug
until gastric transit is complete can reduce the incidence of a
range of gastrointestinal adverse side effects including nausea,
vomiting, dyspepsia, abdominal pain, diarrhea and ileus. Second, by
sustaining release of the active drug over 2 or more hours to as
long as 24 hours, peak drug levels are reduced relative to the peak
drug levels observed for the same administered dose using any oral
formulation that does not have sustained or controlled release.
This reduction in peak drug levels can contribute to reductions in
adverse effects that are partially or completely determined by peak
drug levels. These adverse effects include: fluid retention with
the associated reduced rates of excretion of sodium, chloride and
uric acid, edema, hyperglycemia and the associated potential for
progression to ketoacidosis, cataracts and non-ketotic hyperosmolar
coma, headaches, tachycardia and palpitations.
[0277] Also provided herein are controlled release formulations of
K.sub.ATP channel openers, which have one feature from each of A-D
as shown in Table 1.
TABLE-US-00001 TABLE 1 Controlled Release Formulation
Characteristics and Properties A. Unit Form: Tablet or Capsule B.
Dosage/unit: 10-100 mg 100-200 mg 200-300 mg 300-500 mg 500-2000 mg
C. Dosing Once daily (24 hours) Twice daily (24 hours) D. Release
time: 2-4 hrs 4-8 hrs 8-24 hours
[0278] For example, a controlled release composition can be a
tablet containing 25-100 mg of a K.sub.ATP channel opener, such
tablet administered once daily to achieve a controlled release time
of 2-4 hours. All of these formulations can further include the
feature of substantially delaying pharmaceutical active release
until after gastric transit is complete.
[0279] In addition, any of the above formulations from Table 1 can
include at least one feature that improves the solubility or
absorption of the K.sub.ATP channel opener.
[0280] The controlled release formulations provided herein comprise
the active compound (e.g., K.sub.ATP channel opener, optionally in
combination with growth hormone) and a matrix which comprises a
gelling agent that swells upon contact with aqueous fluid. The
active compound(s) entrapped within the gel is(are) slowly released
into the body upon dissolution of the gel. The active compound(s)
can be evenly dispersed within the matrix or can be present as
pockets of drug in the matrix. For example, the drug can be
formulated into small granules which are dispersed within the
matrix. In addition, the granules of drug also can include a
matrix, thus, providing a primary and a secondary matrix as
described in U.S. Pat. No. 4,880,830 to Rhodes.
[0281] The gelling agent preferably is a polymeric material, which
can include, for example, any pharmaceutically acceptable water
soluble or water insoluble slow releasing polymer such as xantham
gum, gelatin, cellulose ethers, gum arabic, locust bean gum, guar
gum, carboxyvinyl polymer, agar, acacia gum, tragacanth, veegum,
sodium alginate or alginic acid, polyvinylpyrrolidone, polyvinyl
alcohol, or film forming polymers such as methyl cellulose (MC),
carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose,
hyroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose
(HPC), hydroxyethyl cellulose (HEC), ethylcellulose (EC), acrylic
resins or mixtures of the above (see e.g., U.S. Pat. No.
5,415,871).
[0282] The gelling agent of the matrix also can be a heterodisperse
gum comprising a heteropolysaccharide component and a
homopolysaccharide component which produces a fast-forming and
rigid gel as described in U.S. Pat. No. 5,399,359. The matrix also
can include a crosslinking agent such as monovalent or multivalent
metal cations to further add rigidity and decrease dissolution of
the matrix, thus further slowing release of drug. The amount of
crosslinking agent to add can be determined using methods routine
to the ordinary skilled artisan.
[0283] The matrix of the controlled release composition also can
include one or more pharmaceutically acceptable excipients
recognized by those skilled in the art, i.e. formulation
excipients. Such excipients include, for example, binders:
polyvinylpyrrolidone, gelatin, starch paste, microcrystalline
cellulose; diluents (or fillers): starch, sucrose, dextrose,
lactose, fructose, xylitol, sorbitol, sodium chloride, dextrins,
calcium phosphate, calcium sulphate; and lubricants: stearic acid,
magnesium stearate, calcium stearate, Precirol.TM. and flow aids
for example talc or colloidal silicon dioxide.
[0284] The matrix of the controlled release composition can further
include a hydrophobic material which slows the hydration of the
gelling agent without disrupting the hydrophilic nature of the
matrix, as described in U.S. Pat. No. 5,399,359. The hydrophobic
polymer can include, for example, alkylcellulose such as
ethylcellulose, other hydrophobic cellulosic materials, polymers or
co-polymers derived from acrylic or methacrylic acid esters,
co-polymers of acrylic and methacrylic acid esters, zein, waxes,
shellac, hydrogenated vegetable oils, waxes and waxy substances
such as carnauba wax, spermaceti wax, candellila wax, cocoa butter,
cetosteryl alcohol, beeswax, ceresin, paraffin, myristyl alcohol,
stearyl alcohol, cetylalcohol and stearic acid. and any other
pharmaceutically acceptable hydrophobic material known to those
skilled in the art.
[0285] The amount of hydrophobic material incorporated into the
controlled release composition is that which is effective to slow
the hydration of the gelling agent without disrupting the
hydrophilic matrix formed upon exposure to an environmental fluid.
In certain preferred embodiments, the hydrophobic material is
included in the matrix in an amount from about 1 to about 20
percent by weight and replaces a corresponding amount of the
formulation excipient. A solvent for the hydrophobic material may
be an aqueous or organic solvent, or mixtures thereof.
[0286] Examples of commercially available alkylcelluloses are
Aquacoat.RTM. (aqueous dispersion of ethylcellulose available from
FMC) and Surelease.RTM. (aqueous dispersion of ethylcellulose
available from Colorcon). Examples of commercially available
acrylic polymers suitable for use as the hydrophobic material
include Eudragit.RTM. RS and RL (co-polymers of acrylic and
methacrylic acid esters having a low content (e.g., 1:20 or 1:40)
of quaternary ammonium compounds).
[0287] The controlled release composition also can be coated to
retard access of liquids to the active compound and/or retard
release of the active compound through the film-coating. The
film-coating can provide characteristics of gastroresistance and
enterosolubility by resisting rapid dissolution of the composition
in the digestive tract. The film-coating generally represents about
5-15% by weight of the controlled release composition. Preferably,
the core by weight represents about 90% of the composition with the
remaining 10% provided by the coating. Such coating can be a
film-coating as is well known in the art and include gels, waxes,
fats, emulsifiers, combination of fats and emulsifiers, polymers,
starch, and the like.
[0288] Polymers and co-polymers are useful as thin film coatings.
Solution coatings and dispersion coatings can be used to coat the
active compound, either alone or combined with a matrix. The
coating is preferably applied to the drug or drug and matrix
combination as a solid core of material as is well known in the
art.
[0289] A solution for coating can include polymers in both organic
solvent and aqueous solvent systems, and typically further
including one or more compounds that act as a plasticizer. Polymers
useful for coating compositions include, for example,
methylcellulose (Methocel.RTM. A; Dow Chemical Co.),
hydroxypropylmethylcellulose with a molecular weight between 1,000
and 4,000,000 (Methocel.RTM. E; Dow Chemical Co. or
Pharmacoat.RTM.; Shin Etsu), hydroxypropyl cellulose with a
molecular weight between 2,000 and 2,000,000, ethyl cellulose,
cellulose acetate, cellulose triacetate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose acetate
trimellitate (Eastman Kodak), carboxymethylethyl cellulose
(Duodcel.RTM.), hydroxypropyl methylcellulose phthalate,
ethylcellulose, methylcellulose and, in general, cellulosic
derivatives, olymethacrylic acid-methacrylic acid co-polymer (Type
A 1:1 Eudragit L100; Type B 1:2 Eudragit 5100; and Type C 1:1
Eudragit L100-55, aqueous dispersion 30% solids, Eudragit L30D),
poly(meth)acryl ester: poly(ethyl acrylate, methyl methacrylate
2:1), Eudragit NE30D aqueous dispersion 30% solids,
polyaminomethacrylate Eudragit E100, poly(trimethylammonioethyl
methacrylate chloride)ammoniomethacrylate co-polymer, Eudragit
RL30D and Eudragit RS30D, carboxyvinyl polymers, polyvinylalcohols,
glucans scleroglucans, mannans, and xanthans.
[0290] Aqueous polymeric dispersions include Eudragit L30D and
RS/RL30D, and NE30D, Aquacoat brand ethyl cellulose, Surelease
brand ethyl cellulose, EC brand N-10F ethyl cellulose, Aquateric
brand cellulose acetate phthalate, Coateric brand Poly(vinyl
acetate phthalate), and Aqacoat brand hydroxypropyl methylcellulose
acetate succinate. Most of these dispersions are latex, pseudolatex
powder or micronized powder mediums.
[0291] A plasticizing agent may be included in the coating to
improve the elasticity and the stability of the polymer film and to
prevent changes in the polymer permeability over prolonged storage.
Such changes may affect the drug release rate. Suitable
conventional plasticizing agents include, for example, diethyl
phthalate, glycerol triacetate, acetylated monoglycerides,
acetyltributylcitrate, acetyltriethyl citrate, castor oil, citric
acid esters, dibutyl phthalate, dibutyl sebacate, diethyloxalate,
diethyl malate, diethylfumarate, diethylphthalate,
diethylsuccinate, diethylmalonate, diethyltartarate,
dimethylphthalate, glycerin, glycerol, glyceryl triacetate,
glyceryltributyrate, mineral oil and lanolin alcohols, petrolatum
and lanolin alcohols, phthalic acid esters, polyethylene glycols,
propylene glycol, rape oil, sesame oil, triacetin, tributyl
citrate, triethyl citrate, and triethyl acetyl citrate, or a
mixture of any two or more of the foregoing. Plasticizers which can
be used for aqueous coatings include, for example, propylene
glycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80,
triethyl citrate, and diethyl d-tartrate.
[0292] A coating solution comprising a mixture of
hydroxypropylmethylcellulose and aqueous ethylcellulose (e.g.
Aquacoat brand) as the polymer and dibutyl sebacate as plasticizer
can be used for coating microparticles. (Aquacoat is an aqueous
polymeric dispersion of ethylcellulose and contains sodium lauryl
sulfate and cetyl alcohol). Preferably, the plasticizer represents
about 1-2% of the composition.
[0293] In addition to the polymers, the coating layer can include
an excipient to assist in formulation of the coating solution. Such
excipients may include a lubricant or a wetting agent. Suitable
lubricants as excipients for the film coating include, for example,
talc, calcium stearate, colloidal silicon dioxide, glycerin,
magnesium stearate, mineral oil, polyethylene glycol, and zinc
stearate, aluminum stearate or a mixture of any two or more of the
foregoing. Suitable wetting agents include, for example, sodium
lauryl sulfate, acacia, benzalkonium chloride, cetomacrogol
emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol,
diethanolamine, docusate sodium, sodium stearate, emulsifying wax,
glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohols,
lecithin, mineral oil, onoethanolamine, poloxamer, polyoxyethylene
alkyl ethers, polyoxyethylene castor oil derivatives,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
stearates, propylene glycol alginate, sorbitan esters, stearyl
alcohol and triethanolamine, or a mixture of any two or more of the
foregoing.
[0294] The specified tablet or capsule formulations of Table 1 may
include co-formulation with an obesity treating drug (in addition
to the K.sub.ATP channel opener). Obesity treating drugs that may
be used include, but are not limited to, sibutramine hydrochloride
(5-30 mg/unit), orlistat (50-360 mg/unit), phentermine
hydrochloride or resin complex (15 to 40 mg/unit), zonisamide (100
to 600 mg/unit) topiramate (64 to 400 mg/unit), naltrexone
hydrochloride (50 to 600 mg/unit), rimonabant (5 to 20 mg/unit),
ADP356 (5 to 25 mg/unit), ATL962 (20 to 400 mg/unit), or A0D9604 (1
to 10 mg/unit). These formulations are preferably used once daily.
For a twice daily dosing, the amount of K.sub.ATP channel opener is
one half the amount included in the once daily formulation and the
coformulated obesity treating drug is half of the amount specified.
Alternative obesity treating drugs may include: selective serotonin
2c receptor agonists, dopamine antagonists, cannabinoid-1 receptor
antagonists, leptin analogues, leptin transport and/or leptin
receptor promoters, neuropeptide Y and agouti-related peptide
antagonists, proopiomelanocortin and cocaine and amphetamine
regulated transcript promoters, melanocyte-stimulating hormone
analogues, melanocortin-4 receptor agonists, and agents that affect
insulin metabolism/activity, which include protein-tyrosine
phosphatase-1B inhibitors, peroxisome proliferator activated
receptor-receptor antagonists, short-acting bromocriptine
(ergoset), somatostatin agonists (octreotide), and adiponectin,
gastrointestinal-neural pathway agents, including those that
increase cholecystokinin activity, increase glucagon-like peptide-1
activity (extendin 4, liraglutide, dipeptidyl peptidase IV
inhibitors), and increase protein YY3-36 activity and those that
decrease ghrelin activity, as well as amylin analogues, agents that
may increase resting metabolic rate ("selective" .beta.-3
stimulators/agonist, uncoupling protein homologues, and thyroid
receptor agonists), melanin concentrating hormone antagonists,
phytostanol analogues, amylase inhibitors, growth hormone
fragments, synthetic analogues of dehydroepiandrosterone sulfate,
antagonists of adipocyte 11Bhydroxysteroid dehydrogenase type 1
activity, corticotropin releasing hormone agonists, inhibitors of
fatty acid synthesis, carboxypeptidase inhibitors,
indanones/indanols, aminosterols, and other gastrointestinal lipase
inhibitors.
[0295] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a diabetes treating drug (in addition
to the K.sub.ATP channel opener). Diabetes treating drugs that may
be used include, but are not limited to acarbose (50 to 300
mg/unit), miglitol (25 to 300 mg/unit), metformin hydrochloride
(300 to 2000 mg/unit), repaglinide (1-16 mg/unit), nateglinide (200
to 400 mg/unit), rosiglitizone (5 to 50 mg/unit), metaglidasen (100
to 400 mg/unit) or any drug that improves insulin sensitivity, or
improves glucose utilization and uptake. These formulations are
preferably used once daily. For a twice daily dosing, the amount of
the K.sub.ATP channel opener is half the amount included in the
once daily formulation and the co-formulated diabetes treating drug
is half of the amount specified.
[0296] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a cholesterol lowering drug.
Cholesterol lowering drugs that may be used include, but are not
limited to pravastatin or simvastatin or atorvastatin or
fluvastatin or rosuvastatin or lovastatin (all at 10 to 80
mg/unit). These formulations are preferably used once daily. For a
twice daily dosing, the amount of K.sub.ATP channel opener is
preferably 25 to 200 mg/unit and the coformulated cholesterol
lowering drug is half of the amount specified.
[0297] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a depression treating drug. Depression
treating drugs that may be used include, but are not limited to
citalopram hydrobromide (10 to 80 mg/unit), escitalopram
hydrobromide (5 to 40 mg/unit), fluvoxamine maleate (25 to 300
mg/unit), paroxetine hydrochloride (12.5 to 75 mg/unit), fluoxetine
hydrochloride (30 to 100 mg/unit), setraline hydrochloride (25 to
200 mg/unit), amitriptyline hydrochloride (10 to 200 mg/unit),
desipramine hydrochloride (10 to 300 mg/unit), nortriptyline
hydrochloride (10 to 150 mg/unit), duloxetine hydrochloride (20 to
210 mg/unit), venlafaxine hydrochloride (37.5 to 150 mg/unit),
phenelzine sulfate (10 to 30 mg/unit), bupropion hydrochloride (200
to 400 mg/unit), or mirtazapine (7.5 to 90 mg/unit). These
formulations are preferably used once daily. For a twice daily
dosing, the amount of K.sub.ATP channel opener is preferably half
the amount included in the once daily formulation and the
coformulated depression treating drug is half of the amount
specified.
[0298] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a hypertension treating drug.
Hypertension treating drugs that may be used include, but are not
limited to enalapril maleate (2.5 to 40 mg/unit), captopril (2.5 to
150 mg/unit), lisinopril (10 to 40 mg/unit), benzaepril
hydrochloride (10 to 80 mg/unit), quinapril hydrochloride (10 to 80
mg/unit), peridopril erbumine (4 to 8 mg/unit), ramipril (1.25 to
20 mg/unit), trandolapril (1 to 8 mg/unit), fosinopril sodium (10
to 80 mg/unit), moexipril hydrochloride (5 to 20 mg/unit), losartan
potassium (25 to 200 mg/unit), irbesartan (75 to 600 mg/unit),
valsartan (40 to 600 mg/unit), candesartan cilexetil (4 to 64
mg/unit), olmesartan medoxamil (5 to 80 mg/unit), telmisartan (20
to 160 mg/unit), eprosartan mesylate (75 to 600 mg/unit), atenolol
(25 to 200 mg/unit), propranolol hydrochloride (10 to 180 mg/unit),
metoprolol tartrate, succinate or fumarate (all at 25 to 400
mg/unit), nadolol (20 to 160 mg/unit), betaxolol hydrochloride (10
to 40 mg/unit), acebutolol hydrochloride (200 to 800 mg/unit),
pindolol (5 to 20 mg/unit), bisoprolol fumarate (5 to 20 mg/unit),
nifedipine (15 to 100 mg/unit), felodipine (2.5 to 20 mg/unit),
amlodipine besylate (2.5 to 20 mg/unit), nicardipine (10 to 40
mg/unit), nisoldipine (10 to 80 mg/unit), terazosin hydrochloride
(1 to 20 mg/unit), doxasoxin mesylate (4 to 16 mg/unit), prazosin
hydrochloride (2.5 to 10 mg/unit), or alfuzosin hydrochloride (10
to 20 mg/unit). These formulations are preferably used once daily.
For a twice daily dosing, the amount of K.sub.ATP channel opener is
preferably half the amount included in the once daily formulation
and the coformulated hypertension treating drug is half of the
amount specified.
[0299] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a diuretic to treat edema. Diuretics
that may be used include, but are not limited to amiloride
hydrochloride (1 to 10 mg/unit), spironolactone (10 to 100
mg/unit), triamterene (25 to 200 mg/unit), bumetanide (0.5 to 4
mg/unit), furosemide (10 to 160 mg/unit), ethacrynic acid or
ethacrynate sodium (all at 10 to 50 mg/unit), tosemide (5 to 100
mg/unit), chlorthalidone (10 to 200 mg/unit), indapamide (1 to 5
mg/unit), hydrochlorothiazide (10 to 100 mg/unit), chlorothiazide
(50 to 500 mg/unit), bendroflumethiazide (5 to 25 mg/unit),
hydroflumethiazide (10 to 50 mg/unit), mythyclothiazide (1 to 5
mg/unit), or polythiazide (1 to 10 mg/unit). These formulations are
preferably used once daily. For a twice daily dosing, the amount of
K.sub.ATP channel opener is preferably half the amount included in
the once daily formulation and the coformulated diuretic is half of
the amount specified.
[0300] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a drug to treat inflammation or pain.
Drugs for treating inflammation or pain that may be used include,
but are not limited to aspirin (100 to 1000 mg/unit), tramadol
hydrochloride (25 to 150 mg/unit), gabapentin (100 to 800 mg/unit),
acetominophen (100 to 1000 mg/unit), carbamazepine (100 to 400
mg/unit), ibuprofen (100 to 1600 mg/unit), ketoprofen (12 to 200
mg/unit), fenprofen sodium (100 to 600 mg/unit), flurbiprofen
sodium or flurbiprofen (both at 50 to 200 mg/unit), or combinations
of any of these with a steroid or aspirin. These formulations are
preferably used once daily. For a twice daily dosing, the amount of
K.sub.ATP channel opener is preferably half the amount included in
the once daily formulation and the coformulated diuretic is half of
the amount specified.
[0301] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a drug to treat obesity associated
comorbidities include those specified above for treating diabetes,
cholesterol, depression, hypertension and edema, or drugs to treat
atherosclerosis, osteoarthritis, disc herniation, degeneration of
knees and hips, breast, endometrial, cervical, colon, leukemia and
prostate cancers, hyperlipidemia, asthma/reactive airway disease,
gallstones, GERD, obstructive sleep apnea, obesity hypoventilation
syndrome, recurrent ventral hernias, menstrual irregularity and
infertility.
[0302] The specified tablet or capsule formulations of Table 1 may
include co-formulation with an anti-psychotic drug the combination
used to treat the psychotic condition and to treat or prevent
weight gain, dyslipidemia or impaired glucose tolerance in the
treated individual. Drugs for treating various psychotic conditions
that may be used include, but are not limited to, lithium or a salt
thereof (250 to 2500 mg/unit), carbamazepine or a salt thereof (50
to 1200 mg/unit), valproate, valproic acid, or divalproex (125 to
2500 mg/unit), lamotrigine (12.5 to 200 mg/unit), olanzapine (5 to
20 mg/unit), clozapine (12.5 to 450 mg/unit), or risperidone (0.25
to 4 mg/unit). These coformulations are preferably intended for
once per day administration. For a twice daily dosing, the amount
of K.sub.ATP channel opener is preferably half the amount included
in the once daily formulation and the coformulated anti-psychotic
is half of the amount specified.
[0303] The specified tablet or capsule formulations of Table 1 may
include co-formulation with a drug to treat or prevent ischemic or
reperfusion injury. Drugs for treating or preventing ischemic or
reperfusion injury that may be used include, but are not limited
to: low molecular weight heparins (dalteparin, enoxaparin,
nadroparin, tinzaparin or danaparoid), ancrd, pentoxifylline,
nimodipine, flunarizine, ebselen, tirilazad, clomethiazole, an AMPA
agonist (GYKI 52466, NBQX, YM90K, zonampanel, orMPQX), SYM 2081,
selfotel, Cerestat, CP-101,606, dextrophan, dextromethorphan,
MK-801, NPS 1502, remacemide, ACEA 1021, GV150526, eliprodil
ifenprodil, lubeluzole, naloxone, nalfemene citicoline,
acetyl-1-carnitine, nifedipine, resveratrol, a nitrone derivative,
clopidogrel, dabigatram, prasugrel, troxoprodil, AGY-94806, or
KAI-9803.
[0304] Provided are formulations administered once or twice daily
to an obese or overweight subject continuously to result in a
circulating concentration of K.sub.ATP channel opener sufficient to
induce weight loss. Weight loss occurs by the preferential loss of
body fat. Additional weight loss can occur when the formulation is
administered in combination with a reduced calorie diet.
[0305] Provided are formulations of K.sub.ATP channel openers
administered as a single dose to an obese, overweight or
obesity-prone subject that result in the inhibition of fasting or
glucose stimulated insulin secretion for about 24 hours or for
about 18 hours.
[0306] Provided are formulations of K.sub.ATP channel openers
administered as a single dose to an obese, overweight or
obesity-prone subject that result in the elevation of energy
expenditure for about 24 hours or for about 18 hours.
[0307] Provided are formulations of K.sub.ATP channel openers
administered as a single dose to an obese, overweight or
obesity-prone subject that result in the elevation of beta
oxidation of fat for about 24 hours or for about 18 hours.
[0308] Provided are formulations of K.sub.ATP channel openers
administered as a single dose to an obese, overweight or
obesity-prone hyperphagic subject that result in the inhibition of
hyperphagia for about 24 hours or for about 18 hours.
[0309] Provided are formulations administered once or twice daily
(per 24 hours) to a subject continuously result in a circulating
concentration of K.sub.ATP channel opener sufficient to induce
either beta-cell rest or improved insulin sensitivity or both. Such
beta-cell rest and improvements in insulin sensitivity can
contribute to effective treatment of type I diabetes, type II
diabetes and prediabetes. Such beta-cell rest and improvements in
insulin sensitivity can contribute to effective restoration of
normal glucose tolerance in type II diabetic and prediabetic
subjects.
[0310] The various pharmaceutical K.sub.ATP channel opener
formulations have a variety of applications, including, but not
limited to: (1) treatment of obesity; (2) prevention of weight gain
in individuals who are predisposed to obesity; (3) treatment of
hyperinsulemia or hyperinsulinism; (4) treatment of hypoglycemia;
(5) treatment of hyperlipidemia, (6) treatment of type II diabetes,
(7) preservation of pancreatic function in type I diabetics; (8)
treatment of metabolic syndrome (or syndrome X); (9) prevention of
the transition from prediabetes to diabetes, (10) correction of the
defects in insulin secretion and insulin sensitivity contributing
to prediabetes and type II diabetes, (11) treatment of polycystic
ovary syndrome, (12) prevention of ischemic or reperfusion injury,
(13) treat weight gain, dyslipidemia, or impairment of glucose
tolerance in subjects treated with antipsychotics drugs, (14)
prevent weight gain, dyslipidemia, or impairment of glucose
tolerance in subjects treated with antipsychotics drugs and (15)
treatment of any disease where hyperlipidemia, hyperinsulemia,
hyperinsulinism, hyperlipidemia, hyperphagia or obesity are
contributing factors to the severity or progression of the disease,
including but not limited to, Prader-Willi Syndrome, Smith-Magenis
syndrome, Froelich's syndrome, Cohen syndrome, Summit Syndrome,
Alstrom, Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome,
hyperlipoproteinemia type I, II, III, and IV, and the like.
[0311] In one embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage once per 24 hours, optionally in combination with growth
hormone, to induce weight loss. In further embodiments, the
individual (a) is not a type I diabetic, (b) is not a type II
diabetic, (c) is not experiencing chronic, recurrent or
drug-induced hypoglycemia, (d) does not have metabolic syndrome, or
(e) is not experiencing malignant hypertension.
[0312] In one embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage twice per 24 hours, optionally in combination with growth
hormone, to induce weight loss. This treatment can be the sole
treatment to induce weight loss. In further embodiments, the
overweight or obese individual (a) does not have an insulin
secreting tumor, (b) is not suffering from Poly Cystic Ovary
Syndrome, (c) is not a type I diabetic, (d) is not a type II
diabetic, (e) does not have metabolic syndrome, (f) is not
experiencing chronic recurrent or drug-induced hypoglycemia, (g)
has not been treated for schizophrenia with haloperidol, or (h) is
not experiencing malignant hypertension. In further embodiments,
the overweight or obese adolescent (a) has not been diagnosed as
being type I or type II diabetic, (b) is not experiencing chronic,
recurrent or drug-induced hypoglycemia, or (c) has not been
diagnosed as having metabolic syndrome.
[0313] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage form three times per 24 hours, optionally in combination
with growth hormone, to induce weight loss. This treatment can be
the sole treatment to induce weight loss. In further embodiments,
the overweight or obese individual (a) does not have an
insulin-secreting tumor, (b) is not suffering from Poly Cystic
Ovary Syndrome, (c) is not a type I diabetic, (d) is not a type II
diabetic, (e) does not have metabolic syndrome, or (f) is not
experiencing chronic, recurrent or drug-induced hypoglycemia.
[0314] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese adolescent as a solid oral
dosage form three times per 24 hours, optionally in combination
with growth hormone, to induce weight loss. This treatment can be
the sole treatment to induce weight loss. In further embodiments,
the overweight or obese adolescent is (a) is a type I or type II
diabetic, (b) is not experiencing chronic, recurrent or
drug-induced hypoglycemia or (c) does not have metabolic
syndrome.
[0315] In another embodiment, a K.sub.ATP channel opener is
administered as a solid oral dosage form three times per 24 hours,
optionally in combination with growth hormone, to induce weight
loss to an overweight or obese adult who (a) is not simultaneously
receiving glucagon injections, triiodothyroxin or furosemide, (b)
is not being treated for schizophrenia with haloperidol, or (c) is
not experiencing malignant hypertension.
[0316] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage form four times per 24 hours, optionally in combination with
growth hormone, to induce weight loss.
[0317] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage form administered from one, two, three or four times per 24
hours, optionally in combination with growth hormone, to induce
weight loss at a daily dose of 50 to 275 mg. In a further
embodiment, the overweight or obese individual individual (a) is
not type I diabetic, (b) is not type II diabetic, (c) is not
suffering chronic, recurrent or drug-induced hypoglycemia, or (d)
does not have metabolic syndrome.
[0318] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obese individual as a solid oral
dosage form administered from one, two, three or four times per 24
hours, optionally in combination with growth hormone, to induce
weight loss at a daily dose of 130 to 275 mg. In a further
embodiment, the overweight or obese individual (a) is not type I
diabetic, (b) is not type II diabetic, (c) is not suffering
chronic, recurrent or drug-induced hypoglycemia, or (d) does not
have metabolic syndrome.
[0319] In another embodiment, a K.sub.ATP channel opener is
administered to an overweight or obesity prone individual as a
solid oral dosage form one, two, three or four times per 24 hours,
optionally in combination with growth hormone, to maintain a weight
loss, as it is preferable to maintain weight in an obese individual
once some weight loss has occurred when the alternative is to
regain weight. In a further embodiment, the administered daily dose
of the K.sub.ATP channel opener is 50 to 275 mg.
[0320] In other embodiments, a K.sub.ATP channel opener is
administered as a solid oral dosage form to an overweight, obese,
or obesity prone individual, optionally in combination with growth
hormone, to (a) elevate energy expenditure, (b) elevate beta
oxidation of fat, or (c) reduce circulating triglyceride
concentrations.
[0321] In other embodiments, a solid oral dosage of a K.sub.ATP
channel opener is administered on a prolonged basis to an
individual in need thereof to induce the loss of 25%, 50%, or 75%
of initial body fat.
[0322] In another embodiment, a solid oral dosage of a K.sub.ATP
channel opener is administered on a prolonged basis to an
individual in need thereof, optionally in combination with growth
hormone, to induce (a) the preferential loss of body fat or (b) the
preferential loss of visceral body fat.
[0323] In additional embodiments, a solid oral dosage of a
K.sub.ATP channel opener is administered on a prolonged basis one,
two or three times per 24 hours at daily doses of 50 to 275 mg to
an individual, optionally in combination with growth hormone, to
(a) induce the loss of 25%, 50% or 75% of initial body fat, (b)
induce the preferential loss of body fat, or (c) induce the
preferential loss of visceral fat.
[0324] In another embodiment, a solid oral dosage of a K.sub.ATP
channel opener is administered to an individual, optionally in
combination with growth hormone, to induce the preferential loss of
body fat and to induce reduction in circulating triglycerides.
[0325] In another embodiment, a solid oral dosage of a K.sub.ATP
channel opener is co-administered with growth hormone.
[0326] In yet another embodiment, a solid oral dosage of a
K.sub.ATP channel opener is co-administered with growth hormone and
optionally one or more of sibutramine, orlistat, rimonabant, an
appetite suppressant, an anti-depressant, an anti-epileptic, a
diuretic that is not furosemide, a drug that induces weight loss by
a mechanism that is distinct from a K.sub.ATP channel opener, a
drug that induces weight loss by a mechanism that is distinct from
a K.sub.ATP channel opener but is not metformin, furosemide or
triiodothyroxin, or a drug that lowers blood pressure, to induce
weight loss and/or treat obesity associated comorbidities in an
overweight, obese, or obesity prone individual. In further
embodiments, the overweight, obese, or obesity prone individual (a)
is a type I diabetic, (b) is not a type II diabetic, (c) is not
suffering from chronic, recurrent or drug-induced hypoglycemia, or
(d) does not have metabolic syndrome.
[0327] In another embodiment a solid oral dosage of a K.sub.ATP
channel opener is co-administered with growth hormone and
optionally one or more of an anti-depressant, a drug that lowers
blood pressure, a drug that lowers cholesterol, a drug that raises
HDL, an anti-inflammatory that is not a Cox-2 inhibitor, a drug
that lowers circulating triglycerides, to an overweight, obese, or
obesity prone individual to induce weight loss and/or treat obesity
associated comorbidities. In further embodiments, the overweight,
obese, or obesity prone individual (a) is not a type I diabetic,
(b) is not a type II diabetic, (c) is not suffering from chronic,
recurrent or drug-induced hypoglycemia, or (d) does not have
metabolic syndrome.
[0328] In another embodiment, a solid oral dosage of a K.sub.ATP
channel opener is co-administered with growth hormone and
optionally one or more of a drug that lowers blood pressure, a drug
that lowers cholesterol, a drug that raises HDL, an
anti-inflammatory that is not a Cox-2 inhibitor, a drug that lowers
circulating triglycerides, to maintain weight and/or treat obesity
associated comorbidities in an overweight, obese, or obesity prone
individual, as it is preferable to maintain weight in an obese
individual once some weight loss has occurred when the alternative
is to regain weight. In further embodiments, the overweight, obese,
or obesity prone individual (a) is not a type I diabetic, (b) is
not a type II diabetic, (c) is not suffering from chronic,
recurrent or drug-induced hypoglycemia, or (d) does not have
metabolic syndrome.
[0329] In additional embodiments, a tablet formulation of a
K.sub.ATP channel opener is used to administer a therapeutically
effective dose of a K.sub.ATP channel opener to an obese,
overweight or obesity prone individual in need thereof to treat
obesity, to (a) provide beta cell rest, (b) treat type I or type II
diabetes, or (c) prevent the occurrence of diabetes.
[0330] In additional embodiments, a solid oral dosage form or
tablet formulation of a K.sub.ATP channel opener is co-administered
with growth hormone and optionally one or more of Phentermine or a
derivative thereof to an obese adult or adolescent to induce weight
loss and/or treat obesity and obesity-associated co-morbidities. In
further embodiments, a solid oral dosage form or tablet formulation
of a K.sub.ATP channel opener is co-administered with Phentermine
or a derivative, optionally in combination with growth hormone,
thereof to an obese adult or adolescent to treat metabolic syndrome
in a patient in need thereof.
[0331] In further embodiments, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener at doses of 50 to 275
mg/day is co-administered with growth hormone and optionally one or
more of Phentermine or a derivative thereof at daily doses of 15 to
37.5 mg to an overweight or obese individual to induce weight loss,
to treat metabolic syndrome, or to induce weight loss and treat
obesity-associated co-morbidities. In another embodiment, a tablet
formulation is co-administered with growth hormone and optionally
one or more of Phentermine or a derivative thereof to treat
metabolic syndrome in a patient.
[0332] In another embodiment, a quick dissolving formulation of a
K.sub.ATP channel opener, optionally in combination with growth
hormone, is used to provide a therapeutically effective dose to a
patient in need thereof.
[0333] In further embodiments, a K.sub.ATP channel opener is
administered, optionally in combination with growth hormone, once
per 24 hours at doses of 125 mg to 275 mg to an overweight or obese
individual who is not type II diabetic and is not being treated for
nighttime hypoglycemia.
[0334] In further embodiments, a K.sub.ATP channel opener is
formulated as a tablet or capsule for oral administration. The
tablet or capsule may be co-formulated with metformin. In another
embodiment, a K.sub.ATP channel opener is formulated as an oral
suspension, and the oral suspension may be further encapsulated in
another embodiment.
[0335] In another embodiment, a pharmaceutical salt of a K.sub.ATP
channel opener is formulated as a tablet or capsule for oral
administration, or as an oral suspension or as an oral solution, or
as an oral solution that is encapsulated. If the opener is
diazoxide, the salt, is preferably not a sodium salt.
[0336] In another embodiment a K.sub.ATP channel opener is
co-formulated with hydrochlorothiazide, chlorothiazide,
cyclothiazide, benzthiazide, metyclothiazide, bendroflumethiazide,
hydroflumethiazide, trichlormethiazide, or polythiazide in a
pharmaceutical formulation suitable for oral administration.
[0337] Upon administration of the formulations provided herein to
humans or animals, some or all of the following effects are
observed: (1) the production of lipoprotein lipase by adipocytes is
reduced; (2) enhanced lipolysis by adipocytes; (3) expression of
fatty acid synthase by adipocytes is reduced; (4) glyceraldehydes
phosphate dehydrogenase activity of adipocytes is reduced; (5)
little or no new triglycerides are synthesized and stored by
adipocytes; (6) enhanced expression of .beta..sub.3 Adrenergic
Receptor (.beta..sub.3AR) an improvement in the adrenergic function
in adipocytes; (7) reduced glucose stimulated secretion of insulin
by pancreatic B-cells; (8) decreased insulinemia; (9) enhanced
blood glucose levels; (10) increased expression of Uncoupling
Protein 1 in adipocytes; (11) enhanced thermogenesis in white and
brown adipose tissue; (12) reduction of plasma triglyceride
concentration; (13) decrease in circulating leptin concentrations;
(14) up-regulation of insulin receptors; (15) enhanced glucose
uptake; (16) reduced adipocyte hyperplasia; (17) reduced adipocyte
hypertrophy; (18) reduced rates of conversion of preadipocytes to
adipocytes; (19) reduced rates of hyperphagia, (20) increased
protection of CNS, cardiac and other tissues from ischemic or
reperfusion injury, (21) improved insulin sensitivity, (22)
elevated CSF insulin concentrations, (23) elevated circulating
adiponectin concentrations, (25) reduced circulating triglyceride
concentrations, (26) enhancement of beta-cell rest, and/or (27)
increase in lean body mass.
[0338] Threshold concentrations of the current invention include
those circulating concentrations of K.sub.ATP channel openers,
optionally in combination with growth hormone, resulting from the
administration of the drug as an i.v. formulation, an immediate
release oral formulation, a controlled release formulation, a
transdermal formulation, or an intranasal formulation to an
overweight or obese individual which results in (1) measurable
suppression of fasting insulin levels, (2) suppression of fasting
insulin levels by at least 20% from the baseline measurement in the
same individual prior to treatment with a K.sub.ATP channel
openers, (3) suppression of fasting insulin levels by at least 30%
from the baseline measurement in the same individual prior to
treatment with K.sub.ATP channel openers, (4) suppression of
fasting insulin levels by at least 40% from the baseline
measurement in the same individual prior to treatment with a
K.sub.ATP channel openers, (5) suppression of fasting insulin
levels by at least 50% from the baseline measurement in the same
individual prior to treatment with K.sub.ATP channel openers, (6)
suppression of fasting insulin levels by at least 60% from the
baseline measurement in the same individual prior to treatment with
K.sub.ATP channel openers, (7) suppression of fasting insulin
levels by at least 70% from the baseline measurement in the same
individual prior to treatment with K.sub.ATP channel openers, (8)
suppression of fasting insulin levels by at least 80% from the
baseline measurement in the same individual prior to treatment with
K.sub.ATP channel openers, (9) loss of weight, (10) elevation of
resting energy expenditure, or (11) elevation of the oxidation of
fat or fatty acids.
[0339] Threshold effects of the current invention include those
circulating concentrations of K.sub.ATP channel openers resulting
from the administration of an i.v. formulation of the drug, or an
immediate release oral formulation of the drug, or a controlled
release formulation of the drug, or a sustained release
formulation, or a transdermal formulation, or an intranasal
formulation of the drug to an obesity prone individual which result
in (1) the loss of weight, and (2) the maintenance of weight.
[0340] Threshold effects of the current invention include those
circulating concentrations of K.sub.ATP channel openers resulting
from the administration of an i.v. formulation of the drug, or an
immediate release oral formulation of the drug, or a controlled
release formulation of the drug, or a sustained release
formulation, or a transdermal formulation, or an intranasal
formulation of the drug to a prediabetic individual which result in
prevention of the transition to diabetes.
[0341] Threshold effects of the current invention include those
circulating concentrations of K.sub.ATP channel openers resulting
from the administration of an i.v. formulation of the drug, or an
immediate release oral formulation of the drug, or a controlled
release formulation of the drug, or a sustained release
formulation, or a transdermal formulation, or an intranasal
formulation of the drug to a individual with type 1 diabetes which
result in beta cell rest.
[0342] The mode of action by which weight is maintained or lost
resulting from the prolonged administration of K.sub.ATP channel
openers to overweight, obese or obesity prone individuals as
provided herein includes, but is not limited to one or more of (1)
enhanced energy expenditure, (2) enhanced oxidation of fat and
fatty acids, (3) the enhancement of lipolysis in adipose tissue,
(4) enhanced glucose uptake by tissues, enhanced insulin
sensitivity, (5) improved beta adrenergic response, and (6)
increase in lean body mass. The mode of action by which weight is
maintained or lost resulting from the prolonged administration of
K.sub.ATP channel openers to obese or obesity prone individuals as
provided herein may also include the suppression of appetite.
[0343] Prolonged administration of pharmaceutical formulations of
K.sub.ATP channel openers to overweight or obese humans or animals,
optionally in combination with growth hormone, results in
substantial and sustained weight loss including some or all of the
following effects: (1) preferential loss of body fat; (2) loss of
greater than 25% of initial body fat mass; (3) loss of greater than
50% of initial body fat mass; (4) loss of greater than 75% of
initial body fat mass; (5) significant increase in resting energy
expenditure; (6) increase in the oxidation of fat and fatty acids;
(7) reduction in blood pressure; (8) production of lipoprotein
lipase by adipocytes is reduced; (9) enhanced lipolysis by
adipocytes; (10) expression of fatty acid synthase by adipocytes is
reduced; (11) glyceraldehydes phosphate dehydrogenase activity of
adipocytes is reduced; (12) little or no new triglycerides are
synthesized and stored by adipocytes; (13) enhanced expression of
133 Adrenergic Receptor (133AR) and an improvement in the
adrenergic function in adipocytes; (14) reduced glucose stimulated
secretion of insulin by pancreatic B-cells; (15) decreased
insulinemia; (16) enhanced blood glucose levels; (17) increased
expression of Uncoupling Protein 1 in adipocytes; (18) enhanced
thermogenesis in white and brown adipose tissue; (19) reduction of
plasma triglyceride concentration; (20) decrease in circulating
leptin concentrations; (21) up-regulation of insulin receptors;
(22) enhanced glucose uptake; (23) reduced adipocyte hyperplasia;
(24) reduced adipocyte hypertrophy; (25) reduced rates of
conversion of preadipocytes to adipocytes; (26) reduced rates of
hyperphagia; (27) the sequential loss first of the metabolically
most active adipose tissue (visceral), followed by the loss of less
metabolically active adipose tissue, (28) elevation of circulating
adiponectin concentrations, (29) elevation of cerebrospinal fluid
insulin levels, (30) enhanced islet insulin mRNA and insulin
content, (31) enhanced metabolic efficiency of insulin, or (32)
increase in lean body mass.
[0344] Prolonged administration of formulations of K.sub.ATP
channel openers, optionally in combination with growth hormone, to
obesity prone humans or animals, including individuals who have
undergone various types of bariatric surgery, results in sustained
maintenance of weight including some or all of the following
effects: (1) increased resting energy expenditure; (2) increase in
the oxidation of fat and fatty acids; (3) reduction in blood
pressure; (4) production of lipoprotein lipase by adipocytes is
reduced; (5) enhanced lipolysis by adipocytes; (6) expression of
fatty acid synthase by adipocytes is reduced; (7) glyceraldehyde
phosphate dehydrogenase activity of adipocytes is reduced; (8)
little or no new triglycerides are synthesized and stored by
adipocytes; (9) enhanced expression of .beta..sub.3 Adrenergic
Receptor (.beta..sub.3AR) and improvement in the adrenergic
function in adipocytes; (10) reduced glucose stimulated secretion
of insulin by pancreatic B-cells; (11) decreased insulinemia; (12)
enhanced blood glucose levels; (13) increased expression of
Uncoupling Protein 1 in adipocytes; (14) enhanced thermogenesis in
white and brown adipose tissue; (15) reduction of plasma
triglyceride concentration; (16) decreased circulating leptin
concentration; (17) up-regulation of insulin receptors; (18)
enhanced glucose uptake; (19) reduced adipocyte hyperplasia; (20)
reduced adipocyte hypertrophy; (21) reduced rates of conversion of
preadipocytes to adipocytes; and (22) reduced rates of hyperphagia,
(23) elevated circulating adiponectin concentration, (24) elevated
cerebrospinal fluid insulin levels, (25) enhanced islet insulin
mRNA and insulin content, or (26) enhanced metabolic efficiency of
insulin.
[0345] Immediate or prolonged administration of formulations of
K.sub.ATP channel openers, optionally in combination with growth
hormone, to prediabetic or type I diabetic humans or animals
results in the prevention of beta cell failure, improved glycemic
control, and prevention of the transition from prediabetes to
diabetes including some or all of the following effects: (1)
increase in resting energy expenditure; (2) increase in the
oxidation of fat and fatty acids; (3) reduction in blood pressure;
(4) production of lipoprotein lipase by adipocytes is reduced; (5)
enhanced lipolysis by adipocytes; (6) expression of fatty acid
synthase by adipocytes is reduced; (7) glyceraldehyde phosphate
dehydrogenase activity of adipocytes is reduced; (8) little or no
new triglycerides are synthesized and stored by adipocytes; (9)
enhanced expression of 133 Adrenergic Receptor (133AR) and an
improvement in the adrenergic function in adipocytes; (10) reduced
glucose stimulated secretion of insulin by pancreatic B-cells; (11)
decreased insulinemia; (12) enhanced blood glucose levels; (13)
increased expression of Uncoupling Protein 1 in adipocytes; (14)
enhanced thermogenesis in white and brown adipose tissue; (15)
reduction of plasma triglyceride concentration; (16) decreased
circulating leptin concentrations; (17) up-regulation of insulin
receptors; (18) enhanced glucose uptake; (19) reduced adipocyte
hyperplasia; (20) reduced adipocyte hypertrophy; (21) reduced rates
of conversion of preadipocytes to adipocytes; (22) reduced rates of
hyperphagia, (23) elevated circulating adiponectin concentrations,
(24) elevated cerebrospinal fluid insulin levels, (25) enhanced
islet insulin mRNA and insulin content, or (26) enhanced metabolic
efficiency of insulin.
[0346] Immediate or prolonged administration of formulations of
K.sub.ATP channel openers, optionally in combination with growth
hormone, to humans or animals that are at risk for myocardial
infarct, or stroke or undergoing a surgical procedure that restores
blood flow to heart or brain results in improved therapeutic
outcomes post-surgically, or following the occurrence of myocardial
infarct or stroke by improving the survival of tissue after blood
flow is restored, reduced stunning of tissue, and altering the
nature of the inflammatory responses.
[0347] Pharmaceutical formulations as provided herein are designed
to be used in the treatment of obesity, hyperlipidemia,
hypertension, weight maintenance, type I diabetes, prediabetes,
type II diabetes, or any condition where weight loss, reduction in
circulating triglycerides or beta cell rest contributes to
therapeutic outcomes provide for a range of critical changes in
pharmacodynamic and pharmacokinetic responses to administered doses
of K.sub.ATP channel openers, optionally in combination with growth
hormone, which changes include one or more of the following: (1)
extending the pharmacodynamic effect of an administered dose to
greater than 24 hours as measured by the suppression of insulin
secretion, (2) providing for substantial uptake of the active
pharmaceutical ingredient in the small intestine, (3) providing for
substantial uptake of the active pharmaceutical ingredient in the
large intestine, (4) result in lowered C.sub.max versus current
oral suspension or capsule products for the same administered dose
of active pharmaceutical ingredient, (5) provide for circulating
concentrations of unbound active pharmaceutical ingredient above
threshold concentrations for 24 or more hours from a single
administered dose, and (6) provide for more consistent drug
absorption by treated individuals as compared to existing capsule
formulations.
[0348] Pharmaceutical co-formulations of the current invention
designed to treat a range of conditions in humans and animals
include the combination of K.sub.ATP channel openers with growth
hormone and optionally one or more of: (1) a diuretic, (2) a drug
that lowers blood pressure, (3) a drug that suppresses appetite,
(4) a cannabinoid receptor antagonist, (5) a drug that suppresses
that action of gastric lipases, (6) any drug that is used to induce
weight loss, (7) a drug that lowers cholesterol, (8) a drug that
lowers LDL bound cholesterol, (9) a drug that improves insulin
sensitivity, (10) a drug that improves glucose utilization or
uptake, (11) a drug that reduces incidence of atherosclerotic
plaque, (12) a drug that reduces inflammation, (13) a drug that is
antidepressant, (14) a drug that is an anti-epileptic, or (15) a
drug that is an anti-psychotic.
[0349] Treatment of humans or animals of the current invention
using pharmaceutical formulations of K.sub.ATP channel openers,
optionally in combination with growth hormone, result in reduced
incidence of adverse side effects including but not limited to
edema, fluid retention, reduced rates of excretion of sodium,
chloride, and uric acid, hyperglycemia, ketoacidosis, nausea,
vomiting, dyspepsia, ileus and headaches. These reductions in
frequency of adverse side effects are achieved by: (1) initiating
dosing of individuals at subtherapeutic doses and in a step wise
manner increasing the dose daily until the therapeutic dose is
achieved where the number of days over which the step up in dose is
effected is 2 to 10, (2) use of the lowest effective dose to
achieve the desired therapeutic effect, (3) use of a pharmaceutical
formulation that delays release of active until gastric transit is
complete, (4) use of a pharmaceutical formulation that delays
release of active until gastric transit is complete, (5) use of a
pharmaceutical formulation that results in lower circulating peak
drug levels as compared to an immediate release oral suspension or
capsule formulation for the same administered dose, and (6)
optimizing the timing of administration of dose within the day and
relative to meals.
[0350] Treatment of patients suffering from Prader-Willi Syndrome,
Smith-Magenis syndrome, Froelich's syndrome, Cohen syndrome, Summit
Syndrome, Alstrom, Syndrome, Borjesen Syndrome, Bardet-Biedl
Syndrome, and hyperlipoproteinemia type I, II, III, and IV with the
current invention using pharmaceutical formulations of K.sub.ATP
channel openers, optionally in combination with growth hormone,
result in some or all of the following therapeutic outcomes: (1)
weight loss, (2) reduced rates of weight gain, (3) inhibition of
hyperphagia, (4) reduced incidence of impaired glucose tolerance,
prediabetes or diabetes, (5) reduced incidence of congestive heart
failure, (6) reduced hypertension, and (7) reduced rates of all
cause mortality.
[0351] Treatment of prediabetic subjects with the current invention
using pharmaceutical formulations of K.sub.ATP channel openers,
optionally in combination with growth hormone, result in some or
all of the following therapeutic outcomes: (1) weight loss, (2)
restoration of normal glucose tolerance, (3) delayed rates of
progression to diabetes, (4) reduced hypertension, and (5) reduced
rates of all cause mortality.
[0352] Treatment of diabetic subjects with the current invention
using pharmaceutical formulations of K.sub.ATP channel openers,
optionally in combination with growth hormone, result in some or
all of the following therapeutic outcomes: (1) weight loss, (2)
restoration of normal glucose tolerance, (3) delayed rates of
progression of diabetes, (4) improvements in glucose tolerance, (5)
reduced hypertension, and (6) reduced rates of all cause
mortality.
[0353] Co-administration of drugs with formulations of K.sub.ATP
channel openers in the treatment of diseases of overweight, obese
or obesity prone human and animal subjects involves the
co-administration of a pharmaceutically acceptable formulation of
K.sub.ATP channel openers with an acceptable formulation of growth
hormone and optionally one or more of: (1) Sibutramine, (2)
orlistat, (3) Rimonabant, (4) a drug that is an appetite
suppressant, (5) any drug used to induce weight loss in an obese or
overweight individual, (6) a non-thiazide diuretic, (7) a drug that
lowers cholesterol, (8) a drug that raises HDL cholesterol, (9) a
drug that lowers LDL cholesterol, (10) a drug that lowers blood
pressure, (11) a drug that is an anti-depressant, (12) a drug that
improves insulin sensitivity, (13) a drug that improves glucose
utilization and uptake (14) a drug that is an anti-epileptic, (15)
a drug that is an anti-inflammatory, or (16) a drug that lowers
circulating triglycerides.
[0354] Co-administration of drugs with formulations of K.sub.ATP
channel openers in the treatment or prevention of weight gain,
dyslipidemia, or impaired glucose tolerance in subjects treated
with antipsychotics drugs involve the co-administration of a
pharmaceutically acceptable formulation of K.sub.ATP channel
openers with growth hormone and optionally one or more of an
acceptable formulation of: lithium, carbamazepine, valproic acid
and divalproex, and lamotrigine, antidepressants generally
classified as monoamine oxidase inhibitors including isocarboxazid,
phenelzine sulfate and tranylcypromine sulfate, tricyclic
antidepressants including doxepin, clomipramine, amitriptyline,
maproiline, desipromine, nortryptyline, desipramine, doxepin,
trimipramine, imipramine and protryptyline, tetracyclic
antidepressants including mianserin, mirtazapine, maprotiline,
oxaprotline, delequamine, levoprotline, triflucarbine, setiptiline,
lortalaline, azipramine, aptazapine maleate and pirlindole, and
major tranquilizers and atypical antipsychotics including
paloproxidol, perphenazine, thioridazine, risperidone, clozapine,
olanzapine and chlorpromazine.
[0355] In one embodiment, a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered to an overweight
or obese individual as an oral suspension, or an immediate release
capsule or tablet or a controlled release formulation or a
transdermal formulation or an intranasal formulation to reach and
maintain the threshold concentration required to measurably reduce
fasting insulin levels for a prolonged period. Preferably the
K.sub.ATP channel opener formulation reduces fasting insulin levels
by at least 20%, more preferably by at least 30%, more preferably
by at least by 40%, more preferably by at least 50%, more
preferably by at least by 60% more preferably by at least by 70%,
and more preferably by at least 80%. Fasting insulin levels are
commonly measured using the glucose tolerance test (OGTT). After an
overnight fast, a patient ingests a known amount of glucose.
Initial glucose levels are determined by measuring pre-test glucose
levels in blood and urine. Blood insulin levels are measured by a
blood is draw every hour after the glucose is consumed for up to
three hours. In a fasting glucose assay individuals with plasma
glucose values greater than 200 mg/dl at 2 hours post-glucose load
indicate an impaired glucose tolerance.
[0356] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation to reach and maintain the threshold concentration
required to induce weight loss for a prolonged period.
[0357] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation to reach and maintain the threshold concentration
required to elevate resting energy expenditure for a prolonged
period.
[0358] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation to reach and maintain the threshold concentration
required to elevate fat and fatty acid oxidation for a prolonged
period.
[0359] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an obesity prone individual as an oral suspension, or an immediate
release capsule or tablet or a controlled release formulation or a
transdermal formulation or an intranasal formulation to reach and
maintain the threshold concentration required to induce weight loss
for a prolonged period.
[0360] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an obesity prone individual as an oral suspension, or an immediate
release capsule or tablet or a controlled release formulation or a
transdermal formulation or an intranasal formulation to reach and
maintain the threshold concentration required to maintain weight
for a prolonged period.
[0361] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation to reach and maintain a drug concentration above the
threshold concentration required to induce weight loss for a
prolonged period.
[0362] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation for a prolonged period of time to reduce body fat by
more than 25%, more preferably by at least 50%, and more preferably
by at least 75%.
[0363] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation for a prolonged period of time to preferentially reduce
visceral fat deposits.
[0364] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to
an overweight or obese individual as an oral suspension, or an
immediate release capsule or tablet or a controlled release
formulation or a transdermal formulation or an intranasal
formulation for a prolonged period of time to reduce visceral fat
depots and other fat deposits.
[0365] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to a
normoinsulemic overweight or obese individual as an oral
suspension, or an immediate release capsule or tablet or a
controlled release formulation or a transdermal formulation or an
intranasal formulation to reach and maintain a drug concentration
above the threshold concentration required to induce weight loss
for a prolonged period.
[0366] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to a
prediabetic individual as an oral suspension, or an immediate
release capsule or tablet or a controlled release formulation or a
transdermal formulation or an intranasal formulation to reach and
maintain a drug concentration above the threshold concentration
required to prevent the transition to diabetes for a prolonged
period.
[0367] In another embodiment, a K.sub.ATP channel opener,
optionally in combination with growth hormone, is administered to a
type 1 diabetic individual as an oral suspension, or an immediate
release capsule or tablet or a controlled release formulation or a
transdermal formulation or an intranasal formulation to reach and
maintain a drug concentration above the threshold concentration
required to induce beta cell rest for a prolonged period.
[0368] In another embodiment, a single dose of a pharmaceutically
acceptable formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered to an individual
in need thereof that results in circulating concentration of active
drug sufficient to diminish the secretion of insulin for 24 or more
hours.
[0369] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to diminish the secretion of insulin on a continuous
basis.
[0370] In another embodiment, a single dose of a pharmaceutically
acceptable formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered to an individual
in need thereof that results in circulating concentration of active
drug sufficient to elevate non-esterified fatty acids in
circulation for 24 or more hours.
[0371] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to elevate non-esterified fatty acids in circulation on
a continuous basis.
[0372] In another embodiment, a single dose of a pharmaceutically
acceptable formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered to an individual
in need thereof that results in circulating concentration of active
drug sufficient to treat hypoglycemia in circulation for 24 or more
hours.
[0373] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to treat hypoglycemia on a continuous basis.
[0374] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to induce weight loss on a continuous basis.
[0375] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to maintain weight on a continuous basis, as it is
preferable to maintain weight in an obese individual once some
weight loss has occurred when the alternative is to regain
weight.
[0376] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient to reduce circulating triglyceride levels on a
continuous basis.
[0377] In another embodiment, a single dose of a pharmaceutically
acceptable formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered to an individual
in need thereof that results in circulating concentration of active
drug sufficient to reduce or prevent ischemic or reperfusion injury
in circulation for 24 or more hours.
[0378] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is administered over a prolonged
basis to an individual in need thereof no more than once per 24
hours that results in circulating concentration of active drug
sufficient reduce or prevent ischemic or reperfusion injury on a
continuous basis.
[0379] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of diazoxide or its
derivatives that is administered to an individual in need thereof
on a daily basis in which the first dose is known to be
subtherapeutic and daily dose is subsequently increased stepwise
until the therapeutic dose is reached.
[0380] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener that is administered to an individual in need thereof on a
daily basis in which the active ingredient is not released from the
formulation until gastric transit is complete.
[0381] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener that is administered to an individual in need thereof on a
daily basis in which the active ingredient is not released from the
formulation until gastric transit is complete.
[0382] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an individual in need thereof on a daily basis in
which the maximum circulating concentration of active ingredient is
lower than what would be realized by the administration of the same
dose using an oral suspension or capsule formulation.
[0383] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an individual in need thereof on a daily basis in
which the first dose is known to be subtherapeutic and daily dose
is subsequently increased stepwise until the therapeutic dose is
reached, the active ingredient is not released from the formulation
until gastric transit is complete and in which the maximum
circulating concentration of active ingredient is lower than what
would be realized by the administration of the same dose using an
oral suspension or capsule formulation.
[0384] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an overweight or obese individual in need thereof
on a daily basis in which the first dose is known to be
subtherapeutic and daily dose is subsequently increased stepwise
until the therapeutic dose is reached, the active ingredient is not
released from the formulation until gastric transit is complete, in
which the maximum circulating concentration of active ingredient is
lower than what would be realized by the administration of the same
dose using an oral suspension or capsule formulation, and in which
the maximum dose is less than 2.5 mg/kg/day.
[0385] In another embodiment, the adverse effects of frequent
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an overweight or obese individual in need thereof
on a daily basis in which the first dose is known to be
subtherapeutic and daily dose is subsequently increased stepwise
until the therapeutic dose is reached, the active ingredient is not
released from the formulation until gastric transit is complete, in
which the maximum circulating concentration of active ingredient is
lower than what would be realized by the administration of the same
dose using an oral suspension or capsule formulation, and in which
the maximum dose is less than 1.75 mg/kg/day.
[0386] In another embodiment, the treatment of an overweight or
obese individual is optimized for weight loss by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide near zero order release
for at least 12 hours.
[0387] In another embodiment, the treatment of an overweight or
obese individual is optimized for weight loss by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide near zero order release
for at least 18 hours.
[0388] In another embodiment, the treatment of an overweight or
obese individual is optimized for weight loss by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide a rising drug
concentration in circulation for at least 12 hours.
[0389] In another embodiment, the treatment of an overweight or
obese individual is optimized for weight loss by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide a rising drug
concentration in circulation for at least 18 hours.
[0390] In another embodiment, the treatment of an overweight or
obese individual is optimized for weight loss by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to match the pattern of basal insulin
secretion.
[0391] In another embodiment, the frequency of adverse effects upon
treatment with a K.sub.ATP channel opener is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an obesity prone individual in need thereof on a
daily basis in which the first dose is known to be subtherapeutic
and daily dose is subsequently increased stepwise until the
therapeutic dose is reached, the active ingredient is not released
from the formulation until gastric transit is complete, in which
the maximum circulating concentration of active ingredient is lower
than what would be realized by the administration of the same dose
using an oral suspension or capsule formulation, and in which the
maximum dose is less than 2.5 mg/kg/day.
[0392] In another embodiment, the frequency of adverse effects upon
treatment with a K.sub.ATP channel opener, optionally in
combination with growth hormone, is reduced using a
pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, that is
administered to an obesity prone individual in need thereof on a
daily basis in which the first dose is known to be subtherapeutic
and daily dose is subsequently increased stepwise until the
therapeutic dose is reached, the active ingredient is not released
from the formulation until gastric transit is complete, in which
the maximum circulating concentration of active ingredient is lower
than what would be realized by the administration of the same dose
using an oral suspension or capsule formulation, and in which the
maximum dose is less than 1.75 mg/kg/day.
[0393] In another embodiment, the treatment of an obesity prone
individual is optimized for weight maintenance by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide near zero order release
for at least 12 hours.
[0394] In another embodiment, the treatment of an obesity prone
individual is optimized for weight maintenance by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide near zero order release
for at least 18 hours.
[0395] In another embodiment, the treatment of an obesity prone
individual is optimized for weight maintenance by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide a rising drug
concentration in circulation for at least 12 hours.
[0396] In another embodiment, the treatment of an obesity prone
individual is optimized for weight maintenance by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to provide a rising drug
concentration in circulation for at least 18 hours.
[0397] In another embodiment, the treatment of an obesity prone
individual is optimized for weight maintenance by administration of
a pharmaceutically acceptable formulation of a K.sub.ATP channel
opener, optionally in combination with growth hormone, once per 24
hours in which the release of the active ingredient from the
formulation has been modified to match the pattern of basal insulin
secretion.
[0398] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with
sibutramine to an overweight or obese individual to induce weight
loss.
[0399] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with orlistat
to an overweight or obese individual to induce weight loss.
[0400] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with rimonabant
to an overweight or obese individual to induce weight loss.
[0401] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with an
appetite suppressant to an overweight or obese individual to induce
weight loss.
[0402] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with an
anti-depressant to an overweight or obese individual to induce
weight loss.
[0403] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with
anti-epileptic to an overweight or obese individual to induce
weight loss.
[0404] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a
non-thiazide diuretic to an overweight or obese individual to
induce weight loss.
[0405] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that induces weight loss by a mechanism that is distinct from
diazoxide to an overweight or obese individual to induce weight
loss.
[0406] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that lowers blood pressure to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity associated
comorbidities.
[0407] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that lowers cholesterol to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity associated
comorbidities.
[0408] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that raises HDL associated cholesterol to an overweight, obesity
prone or obese individual to induce weight loss and treat obesity
associated comorbidities.
[0409] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that improves insulin sensitivity to an overweight, obesity prone
or obese individual to induce weight loss and treat obesity
associated comorbidities.
[0410] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with an
anti-inflammatory to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity associated
comorbidities.
[0411] In another embodiment, a pharmaceutically acceptable
formulation of a K.sub.ATP channel opener, optionally in
combination with growth hormone, is co-administered with a drug
that lowers circulating triglycerides to an overweight, obesity
prone or obese individual to induce weight loss and treat obesity
associated comorbidities.
[0412] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with
sibutramine in a pharmaceutically acceptable formulation that is
administered to an overweight, obesity prone or obese individual to
induce weight loss and treat obesity-associated co-morbidities.
[0413] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with orlistat
or other active that suppresses the action of gastric lipases in a
pharmaceutically acceptable formulation that is administered to an
overweight, obesity prone or obese individual to induce weight loss
and treat obesity-associated co-morbidities.
[0414] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with a
non-thiazide diuretic in a pharmaceutically acceptable formulation
that is administered to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity-associated
co-morbidities.
[0415] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
appetite suppressant in a pharmaceutically acceptable formulation
that is administered to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity-associated
co-morbidities.
[0416] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with a
cannabinoid receptor antagonist in a pharmaceutically acceptable
formulation that is administered to an overweight, obesity prone or
obese individual to induce weight loss and treat obesity-associated
co-morbidities.
[0417] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
anti-cholesteremic active in a pharmaceutically acceptable
formulation that is administered to an overweight, obesity prone or
obese individual to induce weight loss and treat obesity-associated
co-morbidities.
[0418] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
antihypertensive active in a pharmaceutically acceptable
formulation that is administered to an overweight, obesity prone or
obese individual to induce weight loss and treat obesity-associated
co-morbidities
[0419] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
insulin sensitizing active in a pharmaceutically acceptable
formulation that is administered to an overweight, obesity prone or
obese individual to induce weight loss and treat obesity-associated
co-morbidities.
[0420] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
anti-inflammatory active in a pharmaceutically acceptable
formulation that is administered to an overweight, obesity prone or
obese individual to induce weight loss and treat obesity-associated
co-morbidities.
[0421] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
anti-depressant active in a pharmaceutically acceptable formulation
that is administered to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity-associated
co-morbidities.
[0422] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
anti-epileptic active in a pharmaceutically acceptable formulation
that is administered to an overweight, obesity prone or obese
individual to induce weight loss and treat obesity-associated
co-morbidities.
[0423] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
active that reduces the incidence of atherosclerotic plaque in a
pharmaceutically acceptable formulation that is administered to an
overweight, obesity prone or obese individual to induce weight loss
and treat obesity-associated co-morbidities.
[0424] In another embodiment, K.sub.ATP channel openers, optionally
in combination with growth hormone, are co-formulated with an
active that lowers circulating concentrations of triglycerides in a
pharmaceutically acceptable formulation that is administered to an
overweight, obesity prone or obese individual to induce weight loss
and treat obesity-associated co-morbidities.
[0425] The reduction of circulating triglycerides in an overweight,
obese or obesity prone individual is achieved by the administration
of an effective amount of a solid oral dosage form of a K.sub.ATP
channel opener, optionally in combination with growth hormone.
[0426] A solid oral dosage form of K.sub.ATP channel opener can be
used to administer a therapeutically effective dose of K.sub.ATP
channel opener to an overweight or obesity prone individual in need
thereof to maintain weight, as it is preferable to maintain weight
in an obese individual once some weight loss has occurred when the
alternative is to regain weight.
[0427] A method of inducing loss of greater than 25% of initial
body fat in an overweight or obese individual can be achieved by
the prolonged administration of a solid oral dosage form of a
K.sub.ATP channel opener, optionally in combination with growth
hormone.
[0428] A method of inducing loss of greater than 50% of initial
body fat in an overweight or obese individual can be achieved by
the prolonged administration of a solid oral dosage form of a
K.sub.ATP channel opener, optionally in combination with growth
hormone.
[0429] A method of inducing loss of greater than 75% of initial
body fat in an overweight or obese individual can be achieved by
the prolonged administration of a solid oral dosage form of a
K.sub.ATP channel opener, optionally in combination with growth
hormone.
[0430] A method of inducing preferential loss of visceral fat in an
overweight or obese individual can be achieved by the prolonged
administration of a solid oral dosage form of a K.sub.ATP channel
opener, optionally in combination with growth hormone.
[0431] A method of inducing loss of body fat and reductions in
circulating triglycerides in an overweight or obese individual can
be achieved by the prolonged administration of a solid oral dosage
form of a K.sub.ATP channel opener, optionally in combination with
growth hormone.
[0432] The invention will now be described with reference to the
following non-limiting examples.
EXAMPLES
Example 1: Potassium ATP Channel Activator Containing
Formulations
[0433] 1. Compressed Tablet Formulations
[0434] Diazoxide or a derivative thereof at about 15-30% by weight
is mixed with hydroxypropyl methylcellulose at about 55-80% by
weight, ethylcellulose at about 3-10 wt/vol % and magnesium
stearate (as lubricant) and talc (as glidant) each at less than 3%
by weight. The mixture is used to produce a compressed tablet as
described in Reddy et al., AAPS Pharm Sci Tech 4(4):1-9 (2003). The
tablet may be coated with a thin film as discussed below for
microparticles.
[0435] A tablet containing 100 mg of diazoxide or a derivative
thereof will also contain approximately 400 mg of hydroxypropyl
cellulose and 10 mg of ethylcellulose. A tablet containing 50 mg of
diazoxide or a derivative thereof will also contain approximately
200 mg of hydroxypropyl cellulose and 5 mg of ethylcellulose. A
tablet containing 25 mg of diazoxide or a derivative thereof will
also contain approximately 100 mg of hydroxypropyl cellulose and
2.5 mg of ethylcellulose.
[0436] 2. Encapsulated Coated Microparticle Formulation of
Diazoxide
[0437] Diazoxide or a derivative thereof is encapsulated into
microparticles in accordance with well known methods (see, e.g.
U.S. Pat. No. 6,022,562). Microparticles of between 100 and 500
microns in diameter containing diazoxide or derivative, alone or in
combination with one or more suitable excipient, is formed with the
assistance of a granulator and then sieved to separate
microparticles having the appropriate size. Micriparticles are
coated with a thin film by spray drying using commercial
instrumentation (e.g. Uniglatt Spray Coating Machine). The thin
film comprises ethylcellulose, cellulose acetate,
polyvinylpyrrolidone and/or polyacrylamide. The coating solution
for the thin film may include a plasticizer which may be castor
oil, diethyl phthalate, triethyl citrate and salicylic acid. The
coating solution may also include a lubricating agent which may be
magnesium stearate, sodium oleate, or polyoxyethylenated sorbitan
laurate. The coating solution may further include an excipient such
as talc, colloidal silica or of a mixture of the two added at 1.5
to 3% by weight to prevent caking of the film coated particles.
[0438] 3. Formulation of a Tableted Form of Diazoxide or a
Derivative for Controlled Release
[0439] Prior to mixing, both the active ingredient and
hydroxypropyl methylcellulose (Dow Methocel K4M P) are passed
through an ASTM 80 mesh sieve. A mixture is formed from 1 part
diazoxide or a derivative thereof to 4 parts hydroxypropyl
methylcellulose. After thorough mixing, a sufficient volume of an
ethanolic solution of ethylcellulose as a granulating agent is
added slowly. The quantity of ethylcellulose per tablet in the
final formulation is about 1/10th part. The mass resulting from
mixing the granulating agent is sieved through 22/44 mesh.
Resulting granules are dried at 40.degree. C. for 12 hours and
thereafter kept in a desiccator for 12 hours at room temperature.
Once dry the granules retained on 44 mesh are mixed with 15% fines
(granules that passed through 44 mesh). Talc and magnesium stearate
are added as glidant and lubricant at 2% of weight each. A colorant
is also added. The tablets are compressed using a single punch
tablet compression machine.
[0440] 4. Formulation of a Compression Tableted Form of Diazoxide
or a Derivative Thereof that Provides for Controlled Release
[0441] Diazoxide or a derivative thereof at 20-40% weight is mixed
with 30% weight hydroxypropyl methylcellulose (Dow Methocel K100LV
P) and 20-40% weight impalpable lactose. The mixture is granulated
with the addition of water. The granulated mixture is wet milled
and then dried 12 hours at 110.degree. C. The dried mixture is dry
milled. Following milling, 25% weight ethylcellulose resin is added
(Dow Ethocel 10FP or Ethocel 100FP) followed by 0.5% weight
magnesium stearate. A colorant is also added. The tablets are
compressed using a single punch tablet compression machine
(Dasbach, et al, Poster at AAPS Annual Meeting Nov. 10-14
(2002)).
[0442] 5. Formulation of a Compression Coated Tableted Form of
Diazoxide or a Derivative Thereof that Provides for Controlled
Release.
[0443] The core tablet is formulated by mixing either 100 mg of
diazoxide or a derivative thereof with 10 mg of ethylcellulose (Dow
Ethocel 10FP), or by mixing 75 mg of diazoxide or a derivative
thereof with 25 mg lactose and 10 mg of ethylcellulose (Dow Ethocel
10FP), or by mixing 50 mg of diazoxide or a derivative thereof with
50 mg of lactose and 10 mg of ethylcellulose (Dow Ethocel 10FP).
The core tablets are formed on an automated press with concave
tooling. The compression coating consisting of 400 mg of ethylene
oxide (Union Carbide POLYOX WSR Coagulant) is applied and
compressed to 3000 psi (Dasbach, et al., Poster at AAPS Annual
Meeting Oct. 26-30 (2003)).
[0444] 6. A Controlled Release Dosage Form of Diazoxide or a
Derivative Thereof Using an Osmotically Controlled Release
System
[0445] Diazoxide or a derivative thereof is formulated as an
osmotically regulated release system. In general, two components,
and expandable hydrogel that drives release of the active drug is
assembled with diazoxide or a derivative thereof into a
semipermeable bilaminate shell. Upon assembly a hole is drilled in
the shell to facilitate release of active upon hydration of the
hydrogel.
[0446] A dosage form adapted, designed and shaped as an osmotic
delivery system is manufactured as follows: first, a diazoxide or a
derivative thereof composition is provided by blending together
into a homogeneous blend of polyethylene oxide, of diazoxide or a
derivative thereof and hydroxypropyl methylcellulose. Then, a
volume of denatured anhydrous ethanol weighing 70% of the dry mass
is added slowly with continuous mixing over 5 minutes. The freshly
prepared wet granulation is screened through a 20 mesh screen
through a 20 mesh screen, dried at room temperature for 16 hours,
and again screened through a 20 mesh screen. Finally, the screened
granulation is mixed with 0.5% weight of magnesium stearate for 5
minutes.
[0447] A hydrogel composition is prepared as follows: first, 69%
weight of polyethylene oxide weight, 25% weight of sodium chloride
and 1% weight ferric oxide separately are screened through a 40
mesh screen. Then, all the screened ingredients are mixed with 5%
weight of hydroxypropyl methylcellulose to produce a homogeneous
blend. Next, a volume of denatured anhydrous alcohol equal to 50%
of the dry mass is added slowly to the blend with continuous mixing
for 5 minutes. The freshly prepared wet granulation is passed
through a 20 mesh screen, allowed to dry at room temperature for 16
hours, and again passed through a 20 mesh screen. The screened
granulation is mixed with 0.5% weight of magnesium stearate 5
minutes (see U.S. Pat. No. 6,361,795 by Kuczynski, et al.).
[0448] The diazoxide or a derivative thereof composition and the
hydrogel composition are compressed into bilaminate tablets. First
the diazoxide or a derivative thereof composition is added and
tamped, then, the hydrogel composition is added and the laminae are
pressed under a pressure head of 2 tons into a contacting laminated
arrangement.
[0449] The bilaminate arrangements are coated with a semipermeable
wall (i.e. thin film). The wall forming composition comprises 93%
cellulose acetate having a 39.8% acetyl content, and 7%
polyethylene glycol. The wall forming composition is sprayed onto
and around the bilaminate.
[0450] Finally an exit passageway is drilled through the
semipermeable wall to connect the diazoxide or a derivative thereof
drug lamina with the exterior of the dosage system. The residual
solvent is removed by drying at 50.degree. C. and 50% humidity.
Next, the osmotic systems are dried at 50.degree. C. to remove
excess moisture (see U.S. Pat. No. 6,361,795 by Kuczynski, et
al.).
[0451] 7. Preparation of a Salt of Diazoxide
[0452] A hydrochloride salt of diazoxide is prepared by dissolving
one mole of diazoxide (230.7 g) in 500 ml of Et.sub.2O. Dry HCl is
passed into the solution until the weight of the container is
increased by 36 g. During the addition of the HCl, the HCl salt of
diazoxide precipitates as a powder. The salt is filtered off and
washed with dry Et.sub.2O.
Example 2: In Vivo Obesity Testing
[0453] 1. Obesity Animal Model
[0454] Formulations of diazoxide or derivatives prepared as
described herein can be tested for efficacy in an animal model of
obesity as described by Surwit et al. (Endocrinology 141:3630-3637
(2000)). Briefly, 4-week-old B6 male mice are housed 5/cage in a
temperature-controlled (22.degree. C.) room with a 12-h light, 12-h
dark cycle. The high fat (HF) and low fat (LF) experimental diets
contain 58% and 11% of calories from fat, respectively. A group of
mice are fed the HF diet for the first 4 weeks of the study; the
remaining 15 mice are fed the LF diet. The mice assigned to the LF
diet are maintained on this diet throughout the study as a
reference group of lean control mice. At week 4, all HF-fed mice a
reassigned to 2 groups of mice. The first group remains on the HF
diet throughout the study as the obese control group. The remaining
3 groups of mice are fed the HF diet and administered the
controlled release formulation of diazoxide or derivative at about
150 mg of active per kg per day as a single dose administered by
oral gavage. Animals are weighed weekly, and food consumption is
measured per cage twice weekly until the diets are changed at week
4, whereupon body weight and food intake are determined daily. The
feed efficiency (grams of body weight gained per Cal consumed) is
calculated on a per cage basis. Samples for analysis of insulin,
glucose, and leptin are collected on day 24 (4 days before the
diets are changed), on day 32 (4 days after the change), and
biweekly thereafter. In all cases food is removed 8 h before
samples are collected. Glucose is analyzed by the glucose oxidase
method. Insulin and leptin concentrations are determined by double
antibody RIA. The insulin assay is based on a rat standard, and the
leptin assay uses a mouse standard. At the termination of the
study, a postprandial plasma sample is collected and analyzed for
triglyceride and nonesterified fatty acid concentrations. After 4
weeks of drug treatment, a subset of 10 animals from each group is
killed. The epididymal white adipose tissue (EWAT), retroperitoneal
(RP) fat, interscapular brown adipose tissue (IBAT) fat pads, and
gastrocnemius muscle are removed, trimmed, and weighed. The percent
body fat is estimated from the weight of the epididymal fat pad. A
subset of five animals from each group is injected ip with 0.5 g/kg
glucose. At 30 min postinjection, a plasma sample is collected and
analyzed for glucose content by the glucose oxidase method.
[0455] 2. Treatment of Obesity in Humans
[0456] Formulations of diazoxide or derivatives prepared as
described herein can be tested for efficacy in obese humans. The
study is conducted as described by Alemzadeh (Alemzadeh, et al., J
Clin Endocr Metab 83:1911-1915 (1998)). Subjects consist of
moderate-to-morbidly obese adults with a body mass index (BMI)
greater than or equal to 30 kg/m.sup.2. Each subject undergoes a
complete physical examination at the initial evaluation, body
weight being measured on a standard electronic scale and body
composition by DEXA.
[0457] Before the initiation of the study, all subjects are placed
on a hypocaloric diet for a lead-in period of 1 week. This is
designed to exclude individuals who are unlikely to be compliant
and to ensure stable body weight before treatment. Up to 50
patients are tested at each dosage of drug. Daily dosage is set at
100, 200, and 300 mg/day. The daily dose is divided into 2 doses
for administration. The dose is administered as either one, two or
three 50 mg capsules or tablets at each time of administration.
Individual patients are dosed daily for up to 12 months. Patients
are reviewed weekly, weighed, and asked about any side effects or
concurrent illnesses.
[0458] Twenty-four-hour dietary recall is obtained from each
patient. The dietary recalls are analyzed using a standard computer
software program. All patients are placed on a hypocaloric diet and
encouraged to participate in regular exercise.
[0459] Before commencing, and after completion of the study, the
following laboratory tests are obtained: blood pressure fasting
plasma glucose, insulin, cholesterol, triglycerides, free fatty
acids (FFA), and glycohemoglobin and measures of rate of appearance
and oxidation of plasma derived fatty acids. Additionally, routine
chemistry profiles and fasting plasma glucose are obtained weekly
to identify those subjects with evidence of glucose intolerance
and/or electrolyte abnormalities. Glucose is analyzed in plasma, by
the glucose oxidase method.
[0460] Insulin concentration is determined by RIA using a
double-antibody kit. Cholesterol and triglycerides concentrations
are measured by an enzymatic method. Plama FFA is determined by an
enzymatic colorimetric method. SI was assessed by an iv glucose
tolerance test (IVGTT) using the modified minimal model. After an
overnight fast, a glucose bolus (300 mg/kg) was administered iv,
followed (20 min later) by a bolus of insulin. Blood for
determination of glucose and insulin is obtained from a contra
lateral vein at -30, -15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25, 30,
40, 50, 70, 100, 140, and 180 min. SI and glucose effectiveness
(SG) are calculated using Bergman's modified minimal-model computer
program before and after the completion of the study. Acute insulin
response to glucose is determined over the first 19 min of the
IVGTT, and the glucose disappearance rate (Kg) is determined from
8-19 min of the IVGTT. Body composition is measured by
bioelectrical impedance before and at the completion of the study.
Resting energy expenditure (REE) is measured by indirect
calorimetry after an overnight 12-h fast, with subjects lying
supine for a period of 30 min. Urine is collected over the
corresponding 24 h, for measurement of total nitrogen and
determination of substrate use, before and after the study.
[0461] 3. Treatment of Obesity in Humans by Coadministering
Diazoxide and Phentermine
[0462] Evaluation of a prolonged co-administration of solid oral
dosage form of diazoxide or a derivative thereof and phentermine in
obese humans with a moderate-to-morbidly and a body mass index
(BMI) greater than or equal to 30 kg/m'. Each subject undergoes a
complete physical examination at the initial evaluation, body
weight being measured on a standard electronic scale and body
composition by DEXA.
[0463] Before the initiation of the study, all subjects are placed
on a hypocaloric diet for a lead-in period of 1 week. This is
designed to exclude individuals who are unlikely to be compliant
and to ensure stable body weight before treatment. Up to 100
patients are tested. Daily dosage of diazoxide is set at 200 mg.
The daily dose is divided into 2 doses for administration. The dose
is administered as either a 100 mg capsule or a 100 mg tablet at
each time of administration. Individual patients are dosed daily
for up to 12 months. Phentermine is administered as a single daily
dose of 15 mg. Patients are reviewed every two weeks, weighed, and
asked about any side effects or concurrent illnesses.
[0464] All patients are continued on a hypocaloric diet and
encouraged to participate in regular exercise. Before commencing,
and after completion of the study, laboratory tests as described in
the example above are obtained.
[0465] 4. Prevention of Diabetes in Prediabetic Humans
[0466] The example describes use of diazoxide in a prediabetic
individual to prevent the occurrence of diabetes. Individuals
included in the study all have elevated risk of developing diabetes
as measured by one of two methods. In a fasting glucose assay they
have plasma glucose values between 100 and 125 mg/dl indicating
impaired fasting glucose, or in an oral glucose tolerance test they
have plasma glucose values between 140 and 199 mg/dl at 2 hours
post-glucose load indicating they have impaired glucose tolerance.
Treatment is initiated in any individual meeting either criteria.
Treated individuals receive either 200 mg diazoxide per day as a
100 mg capsule or tablet twice per day or as two 100 mg capsules or
tablets once per day. Placebo treated individuals receive either
one placebo capsule or tablet twice per day or two placebo capsules
or tablets once per day.
[0467] Treatment is continued for one year with OGTT or fasting
glucose measured monthly.
[0468] 5. A Sustained Release Coformulation of Diazoxide HCl and
Metformin HCl Use to Treat Diabetic Patients
[0469] A sustained release co-formulation of diazoxide HCl and
metformin HCl is produced by forming a compressed tablet matrix
that includes 750 mg of metformin HCl and 100 mg of diazoxide HCl.
These active ingredients are blended with sodium carboxymethyl
cellulose (about 5% (w/w)), hypromellose (about 25% (w/w), and
magnesium stearate (<2% (w/w)). The compressed tablet is further
coated with a combination of ethylcellulose (80% (w/w)) and methyl
cellulose (20% (w/w)) as a thin film to control rate of hydration
and drug release.
[0470] Type II diabetic patients are treated with the oral dosage
form by administration of two tablets once per day or one tablet
every 12 hours. Treatment of the patient with the drug is continued
until one of two therapeutic endpoints is reached, or for so long
as the patient derives therapeutic benefit from administration. The
two therapeutic endpoints that would serve as the basis for the
decision to cease treatment include the patient reaching a Body
Mass Index (BMI (kg/m.sup.2)) between 18 and 25 or the
re-establishment of normal glucose tolerance in the absence of
treatment. The patient is monitored periodically for (a) glucose
tolerance using an oral glucose tolerance test, (b) glycemic
control using a standard blood glucose assay, (c) weight gain or
loss, (d) progression of diabetic complications, and (e) adverse
effects associated with the use of these active ingredients.
[0471] 6. Prevention or Treatment of Weight Gain in a Patient
Treated with Olanzapine
[0472] Pharmacotherapy for schizophrenia is initiated for a patient
meeting DSM III-R criteria for schizophrenia. The patient is
administered 10 mg of olanzapine (Zyprexa, Lilly) once per day.
Adjunctive therapy to the patient for schizophrenia includes 250 mg
equivalent of valproic acid as divalproex sodium (Depakote, Abbott
Labs). Weight gain, dyslipidemia and impaired glucose tolerance,
and metabolic syndrome are high frequency adverse events in
patients treated with this combination of anti-psychotics. Weight
gain, dyslipidemia, impaired glucose tolerance or metabolic
syndrome are treated by the co-administration of a therapeutically
effective dose of a K.sub.ATP channel opener. The patient is
treated with administration of 200 mg/day of diazoxide as a once
daily tablet formulation. Diazoxide administration continues until
the weight gain, dyslipidemia, impaired glucose tolerance or
metabolic syndrome is corrected or until treatment of the patient
with olanzapine is discontinued. Dyslipidemia is detected by
measuring circulating concentrations of total, HDL, and LDL
cholesterol, triglycerides and non-esterified fatty acids. Impaired
glucose tolerance is detected through the use of oral or IV glucose
tolerance tests. Metabolic syndrome is detected by measuring its
key risk factors including central obesity, dyslipidemia, impaired
glucose tolerance, and circulating concentrations of key
proinflammatory cytokines.
Example 3: Clinical Study in Obese Pediatric and Adult PWS
Patients
[0473] A single-center, open-label, single-arm clinical study
(PC025) with a double-blind, placebo-controlled, randomized
withdrawal extension has been carried out. Patients were initiated
on a DCCR dose of about 1.5 mg/kg (maximum starting dose of 145 mg)
and were titrated every 14 days to about 2.4 mg/kg, 3.3 mg/kg, and
4.2 mg/kg (maximum dose of 507.5 mg). These DCCR doses are
equivalent to diazoxide doses of 1.03, 1.66, 2.28, and 2.9 mg/kg,
respectively. Patients were up-titrated at each visit at the
discretion of the investigator. Any patient who showed an increase
in resting energy expenditure and/or a reduction in hyperphagia
from Baseline through Day 27 or Day 55 was designated a Responder
and eligible to be randomized in the double-blind phase. Everyone
who completed the open-label phase was a Responder and was
randomized in and completed the double-blind phase. During the
double-blind, placebo-controlled, randomized withdrawal phase,
Responders were randomized in a 1:1 ratio either to continue on
active treatment at the dose they were treated with on Day 55 or to
the placebo equivalent of that dose for an additional 4 weeks (29
days). Non-responders continued open label treatment with DCCR at
the dose they were treated with on Day 55 for an additional 29
days. A total of 12 patients were enrolled in the study.
[0474] Inclusion Criteria: Basic Requirements [0475] Ability to
follow verbal and written instructions with or without assistance
from caregiver [0476] Informed consent form signed by the subject
or their legal guardian [0477] Completed the screening process
between 2 and 4 weeks prior to Baseline Visit
[0478] General Demographic Characteristics [0479] Male and female
patients 10 to 22 years of age, inclusive at the time of dosing
[0480] Genetically confirmed Prader-Willi syndrome [0481] BMI
exceeds the 95.sup.th percentile of the age specific BMI value on
the CDC BMI charts or percent body fat.gtoreq.35% (The body fat
criteria will only be used if there were a measurement made within
12 months of the Screening Visit, and the patient has not lost
weight since the measurement. Under all other circumstances, the
BMI criteria will apply.) [0482] Generally healthy as documented by
the medical history, physical examination, vital sign assessments,
12-lead electrocardiogram (ECG), and clinical laboratory
assessments
[0483] Specific Laboratory Test Results [0484] fasting glucose
.ltoreq.126 mg/dL [0485] HbA1c.ltoreq.6.5%
Endpoints and Statistical Analysis
[0486] Every endpoint is measured in two timeframes: (1) during the
open label treatment phase as change (or percent change) from
Baseline to Day 69; and (2) during the double-blind,
placebo-controlled, randomized withdrawal phase as change (or
percent change) from Day 69 to Day 97.
[0487] Endpoints measured during the open label treatment phase
were analyzed by paired t-test while those measured during the
double-blind, placebo-controlled treatment phase are subjected to
ANOVA and paired t-tests.
[0488] Efficacy endpoints include: hyperphagia (measured using
parent/caregiver responses on a modified Dykens hyperphagia
questionnaire--converted to a numeric score between 0 and 34);
weight; body fat (measured by DEXA); lean body mass (measured by
DEXA); resting energy expenditure (measured by indirect
calorimetry); respiratory quotient (measured by indirect
calorimetry); waist circumference; BMI; ghrelin; leptin;
triglycerides; total cholesterol; HDL cholesterol; non-HDL
cholesterol and LDL cholesterol. Additional information was
collected in a behavioral questionnaire. Tables 2 and 3 summarize
the visits at which each efficacy parameter was measured.
TABLE-US-00002 TABLE 2 Time points for assessment of efficacy
parameters during open-label phase End of Screen- Base- Visit Visit
Visit Visit Open label Parameter ing line 3 4 5 6 treatment
Hyperphagia + + + + + + + Body fat Either at + Lean body screening
+ mass or baseline Weight + + + + + + + REE & RQ + + + + Waist
+ + + + + + + circumference Ghrelin, leptin + + Lipids + +
Behavioral + + questionnaire
TABLE-US-00003 TABLE 3 Time points for assessment of efficacy
parameters during double-blind treatment Day 69 End of Day 97 End
of Open label double blind Parameter Screening Baseline treatment
treatment Hyperphagia + + + + Body fat Either at screening + Lean
body or baseline + mass Weight + + + + REE & RQ + + + Waist + +
+ + circumference Ghrelin, leptin + + Lipids + + + Behavioral + +
questionnaire
Patients in the Study
[0489] Demographic information and relevant medical history for
each patient are shown in Table 4. Eleven of the thirteen subjects
enrolled in clinical study PC025 completed the open-label phase.
All were identified as Responders and were, therefore, randomized
in the double-blind phase of the study. All subjects randomized in
the double-blind phase of the study completed the phase.
[0490] Baseline characteristics of patients enrolled in the study
are provided in Table 5.
TABLE-US-00004 TABLE 4 Demographic information and relevant medical
history for patients enrolled in PC025 PWS Age at GH Patient Sex
Age sub-type diagnosis trt* Relevant medical history BN-01 M 11.6
Deletion 4 wk No acanthosis nigricans, obesity @ 3 yr, asthma,
undescended testes, fatty liver, sleep apnea CP-02 M 16.5 Deletion
3 wk Yes cerebral palsy, obesity @ 2 yr, type 2 diabetes,
gynecomastia, undescended testicle, sleep apnea, asthma @ 1 yr
TJ-03 M 18.6 Deletion 6 wk No obesity @ 3 yr with hyperphagia,
psychiatric illness @ 2 yr, undescended testicle, osteopenia AC-04
F 17.0 Deletion 15 yr No scoliosis, short stature, osteopenia MR-05
F 17.8 Deletion 5.7 yr No scoliosis, strabismus, amenorrhea SD-06 M
16.7 Deletion 3 yr Yes morbid obesity @ 6 yr, sleep apnea,
scoliosis, pulmonary hypertension, undescended testes, strabismus
AS-08 M 11.9 Deletion 10 wk Yes hyperphagia @ 3 yr, dyslipidemia,
opthalmoplegia, osteopenia, scoliosis SP-09 F 21.6 Deletion 6 wk No
scoliosis, sleep apnea, osteopenia, amenorrhea DD-10 M 12.5 UPD 16
wk Yes osteopenia SM-11 F 15.4 Deletion 1 wk Yes psychiatric
disease, osteopenia, scoliosis AD-13 F 14.7 Deletion 4 wk No
obesity @ 5 yr, osteopenia JG-15 M 14.4 Deletion 2 wk Yes obesity @
5 yr NT-16 M 19.3 Deletion 2 wk No Scoliosis, strabismus, sleep
apnea
TABLE-US-00005 TABLE 5 Baseline characteristics of subjects who
were randomized in the double-blind phase of clinical study PC025.
Hyper- Weight Height Percent phagia REE Subject (kg) (cm) body fat
BMI score % RDA RQ CP-02 97.2 166 52.0 35.3 18.5 83% 0.86 AC-04
56.9 151 46.8 25.0 7 84% 0.78 MR-05 113.1 145 59.1 53.8 20.5 83%
0.87 SD-06 133.6 145 53.5 51.5 3 102% 0.84 AS-08 60.9 140 53.4 31.0
25.5 86% 1.03 SP-09 106.8 148 60.7 48.8 10.5 84% 0.72 DD-10 70.8
155 49.3 29.5 32 101% 0.97 SM-11 62.2 140 48.8 31.7 8 97% 0.81
AD-13 103.5 149 56.6 46.6 10 94% 0.85 JG-15 106.3 161 53.7 41.0 16
71% 0.79 NT-16 80.8 177 36.4 25.7 14 100% 0.78 Average 90.4 152.5
51.8 38.2 14.95 89.6%.sup. 0.85
Dosing
[0491] One subject, a treated type 2 diabetic, finished the
open-label treatment period on a dose of 1.5 mg/kg. Of the
remaining 10 subjects, 1 finished the open-label treatment period
at a dose of 2.4 mg/kg, and 3 at 3.3 mg/kg. The last 6 subjects
enrolled in the study finished the open-label treatment phase at a
dose 4.2 mg/kg.
Changes in Body Composition, Waist Circumference and Weight
[0492] Body fat and lean body mass were measured by DEXA at
baseline and again at the end of the open label treatment. Since
DEXA was not run on Day 97, the only body composition measurements
made on the subjects randomized in the double-blind phase occurred
in the period from Baseline to Day 69. The body composition changes
are outlined in Table 6. Changes in body composition by DEXA were
evaluated separately for subjects who were growth hormone treated
and growth hormone naive. These results are shown in Table 6.
[0493] Weight by DEXA was calculated as the sum of body fat and
lean body mass. The ratio of lean body mass to body fat was also
calculated.
TABLE-US-00006 TABLE 6 Changes in body composition by DEXA from
Baseline through Day 69 Parameter n Percent Change p-value All
subjects randomized in the double blind phase Body fat 11 -3.8%
0.011 Lean body mass 11 5.41% 0.001 Lean body mass/fat mass ratio
11 9.82% 0.002 Weight 11 0.67% 0.150 Growth hormone treated
subjects Body fat 6 -3.31% 0.056 Lean body mass 6 5.50% 0.005 Lean
body mass/fat mass ratio 6 9.37% 0.014 Weight 6 0.90% 0.189 Growth
hormone naive subjects Body fat 5 -4.34% 0.083 Lean body mass 5
5.30% 0.055 Lean body mass/fat mass ratio 5 10.36% 0.043 Weight 5
0.39% 0.301
[0494] Treatment with DCCR for 10 weeks had a highly significant
and clinically relevant impact on body composition including
reductions in body fat, increases in lean body mass and a very
marked increase in lean body mass to body fat ratio. Because these
patients had almost equal lean body mass and fat mass at Baseline,
parallel increases in lean body mass and reductions in body fat
result in almost no net change in weight. In general, the changes
in body composition were of similar magnitude in both growth
hormone treated and growth hormone naive subjects.
[0495] The changes in body composition were dose dependent. Those
subjects who completed the open-label treatment phase at a dose of
4.2 mg/kg experienced a 6.3% decrease in fat mass, a 9.2% increase
in lean body mass and a 16.6% increase in the lean body mass to fat
mass ratio.
[0496] Three subjects in the study showed greater than 10% increase
in lean body mass. Every subject showed an increase in lean body
mass/fat mass ratio. More than half of the subjects in the study
showed a >10% increase in the lean body mass/fat mass ratio, and
one showed more than a 20% increase.
[0497] FIGS. 1-4 summarize the percent change in body fat, lean
body mass and lean body mass/fat mass ratio from Baseline through
Day 69.
[0498] Weight and waist circumference were measured during the
physical exam at each visit. This data can be used to evaluate the
change from Baseline through Day 69 for all subjects randomized in
the double-blind phase, by arm for the period from Day 69 through
Day 97 and in those who continued on DCCR in the double-blind phase
from Baseline through Day 97. The results from the period covering
Baseline through Day 69 are summarized in Table 7. The results from
the period covering Day 69 through Day 97 are shown in Table 8. The
results for subjects who continued on DCCR in the double blind
phase from baseline through Day 97 are shown in Table 9.
TABLE-US-00007 TABLE 7 Changes in weight and waist circumference
from Baseline through Day 69 Change/Percent Parameter n change
p-value Weight 11 0.53% 0.317 Waist circumference 11 -3.5 cm
0.003
TABLE-US-00008 TABLE 8 Changes in weight and waist circumference
from Day 69 through Day 97 Change/Percent p-value Parameter Arm n
change comparing arms Weight DCCR 5 -1.7% 0.723 Weight Placebo 6
-1.1% Waist circumference DCCR 5 -2.9 cm 0.047 Waist circumference
Placebo 5 0.25 cm
TABLE-US-00009 TABLE 9 Changes in weight and waist circumference
from Baseline through Day 97 for those treated with DCCR in the
double-blind phase Change Parameter n Through Day 97 p-value Weight
5 0.4% 0.828 Waist circumference 5 -3.7 cm 0.039
[0499] Interestingly, the change in weight from Baseline through
day 69 by DEXA and by the standard weight measurement produces
almost identical results (an increase of 0.67% by DEXA and 0.53% by
the standard approach). In contrast to the lack of change in
weight, there was a statistically significant reduction in waist
circumference through Day 69 in all subjects randomized in the
double-blind phase; through Day 97 for those who continued on DCCR.
The comparison of change in waist circumference between arms
between Day 69 and Day 97, during which the placebo treated
patients showed an incremental increase in waist circumference,
while those who continued on DCCR, showed a notable reduction. The
reduction in waist circumference is consistent with the explanation
that DCCR treated subjects are losing visceral fat.
Changes in Hyperphagia
[0500] The hyperphagia questionnaire was administered at all
visits. This data can be used to evaluate the change from Baseline
through Day 69 for all subjects randomized in the double-blind
phase, by arm for the period from Day 69 through Day 97 and in
those who continued on DCCR in the double-blind phase from Baseline
through Day 97. The results from the period covering Baseline
through Day 69 are summarized in Table 10. The results from the
period covering Day 69 through Day 97 are shown in Table 11. The
results for subjects who continued on DCCR in the double blind
phase from baseline through Day 97 are shown in Table 12.
TABLE-US-00010 TABLE 10 Changes in hyperphagia from Baseline
through Day 69 Parameter n Percent change p-value Hyperphagia 11
-31.6% 0.003
TABLE-US-00011 TABLE 11 Changes in hyperphagia from Day 69 through
Day 97 p-value Parameter Arm n Change comparing arms Hyperphagia
DCCR 5 2.0 0.389 Hyperphagia Placebo 6 0.33
TABLE-US-00012 TABLE 12 Changes in hyperphagia from Baseline
through Day 97 for those treated with DCCR in the double-blind
phase Percent change Parameter n through Day 97 p-value Hyperphagia
5 -29.2% 0.006
[0501] There was a statistically significant reduction in
hyperphagia in all subjects randomized in the double-blind phase
from Baseline through Day 69 and in those who continued on DCCR
through the double-blind phase from Baseline through Day 97.
[0502] DCCR treated patients at the end of 97 days of treatment
showed an improvement in hyperphagia of 29.2% while those that were
treated with DCCR for 69 days followed by 28 days of placebo
treatment showed only a 13.9% improvement in hyperphagia on Day 97.
Thus, at the end of the double-blind phase, DCCR treated patients
showed more than twice the improvement in hyperphagia as did those
who were randomized to placebo in the double-blind phase. Once
patients discontinue from DCCR treatment, given the long half-life
of DCCR (28-32 hours) it takes about 7-10 days to completely clear
from circulation. Verbatim statements were obtained from parents of
subjects in the study suggesting that they had seen their
children's food related behavior deteriorate only in the last
couple of weeks of the study, suggesting a longer double-blind
phase might have resulted in further separation of the arms. In
general, the magnitude of impact on how upset subjects became when
denied food, how easy it was to get them to think about something
else if once denied food, and the impact on the frequency of
stealing food, digging through the trash for food and bargaining
for food were of equivalent or greater magnitude as the overall
impact on the hyperphagia score. DCCR appeared to have lesser
impact on how sneaky or quick subjects were with respect to food
and on how often they got up at night to seek food.
[0503] Improvements in hyperphagia were observed in subjects with
baseline hyperphagia ranging from 29 (-45%) to less than 5 (-33%)
on a 0 to 34 point scale.
[0504] About 25% of the subjects ended the open-label phase with
very low levels of hyperphagia (2 or 3 on a 0 to 34 scale). These
subjects tended to be able to lose more body fat than the average.
Two such subjects, both females, one growth hormone treated and one
growth hormone naive, lost more than 10% of their initial body fat
mass through 10 weeks.
[0505] FIG. 1 shows the change in hyperphagia from Baseline through
Day 69.
Changes in Lipids
[0506] A lipid panel was evaluated at Baseline, and again on Day 69
and Day 97. This data can be used to evaluate the change from
Baseline through Day 69 for all subjects randomized in the
double-blind phase, by arm for the period from Day 69 through Day
97 and in those who continued on DCCR in the double-blind phase
from Baseline through Day 97. The results from the period covering
Baseline through Day 69 are summarized in Table 13. The results for
subjects who continued on DCCR in the double blind phase from
baseline through Day 97 are shown in Table 14.
TABLE-US-00013 TABLE 13 Changes in Lipids from Baseline through Day
69 Parameters n Percent change p-value Total cholesterol 8 -4.0%
0.044 Triglycerides 7 -21.0% 0.084 HDL-C 8 10.8% 0.244 LDL-C 8
-7.0% 0.030 Non HDL-C 8 -6.5% 0.019
TABLE-US-00014 TABLE 14 Median Percent Change in lipids from
Baseline through Day 97 for those treated with DCCR in the
double-blind phase Median Percent change from Parameter Baseline
through Day 97 Total Cholesterol -11.0% Triglycerides -41.8% HDL-C
25.2% LDL-C -7.9% Non-HDL-C -13.4%
[0507] Consistent with previous studies involving DCCR, treatment
of subjects randomized in the double-blind phase with DCCR from
Baseline through Day 69 resulted in a number of statistically
significant changes in lipids including reductions in total
cholesterol, LDL cholesterol and non-HDL cholesterol. Even though
the impact on triglycerides was of larger magnitude, it did not
reach significance because of the smaller n and greater variability
in the population. In general, greater reductions in triglycerides
were seen in those with significant elevations in triglycerides at
Baseline. A similar pattern was observed in those who were treated
with DCCR through the end of the double-blind treatment. The
decreases in total cholesterol, triglycerides, LDL-C and non-HDL-C
were all larger in those who were treated with DCCR longer.
Changes in Leptin and Ghrelin
[0508] Leptin and ghrelin were measured at Baseline and again on
Day 69. The results from Baseline through Day 69 for leptin and
ghrelin are provided in Table 15.
TABLE-US-00015 TABLE 15 Leptin and ghrelin changes from Baseline
through Day 69 Parameter n Percent change p-value Leptin 6 -22.0%
0.061 Ghrelin 6 -15.0% 0.052
[0509] Further evidence for loss of body fat comes from the
analysis of leptin, the results of which are consistent with the
DEXA data and the data on waist circumference. Although not quite
reaching statistical significance, leptin is down more than 20%
from Baseline.
[0510] While ghrelin may or may not contribute substantially to
hyperphagia in PWS, reductions in ghrelin are beneficial in PWS
patients.
Behavioral Changes
[0511] A questionnaire, adapted from the PWS natural history study,
was used to document the presence or absence of 23 PWS-associated
behaviors at Baseline and again on Day 69. These behaviors
generally fell into 4 categories:
[0512] (1) aggressive, threatening and destructive behaviors;
[0513] (2) self-injurious behaviors;
[0514] (3) compulsive behaviors; and
[0515] (4) other behaviors.
The questionnaire was administered at Baseline and again on Day 69.
Discontinuation rates for aggressive, threatening, destructive
behaviors and for all other behaviors are shown in Table 16.
TABLE-US-00016 TABLE 16 Discontinuation rates for various classes
of behavior in clinical study PC025 Behaviors Discontinuation rate
p-value Aggressive, threatening, destructive -62.5% 0.01 All other
PWS associated behaviors -29.8%
[0516] The impact on aggressive, threatening and destructive
behaviors was independent of an impact on hyperphagia.
Changes in Resting Energy Expenditure and Respiratory quotient
[0517] The measurements for resting energy expenditure and
respiratory quotient were quite variable from visit to visit.
Despite the variability, resting energy expenditure and respiratory
quotient appeared to be unchanged from Baseline through Day 69.
Changes in Insulin Sensitivity
[0518] Treatment with DCCR in other clinical studies was associated
with improvements in insulin resistance as measured by changes in
homeostatic model assessment of insulin resistance (HOMA-IR).
Improvements in insulin sensitivity are well documented in the
literature on diazoxide. The subjects enrolled in the double-blind
phase of this study were quite insulin sensitive at Baseline, which
is typical of PWS patients in this age range. Consistent with prior
DCCR clinical studies and the historic diazoxide literature,
treatment with DCCR for 10 weeks resulted in an improvement in
HOMA-IR from 2.61.+-.1.85 at Baseline to 1.46.+-.1.36 on Day 69.
The difference did not reach statistical significance
(p=0.095).
Example 4: Clinical Studies with Smith-Magenis Syndrome
Patients
[0519] In a first example, a Smith-Magenis syndrome patient is
treated with an oral suspension of diazoxide. The initial dose is
approximately 1 mg/kg administered in divided doses. After the
patient has been stably treated with 1 mg/kg for a period of 1 to 2
weeks, the dose is titrated to about 1.5 mg/kg. After the patient
had been stably treated with 1.5 mg/kg for a period of 1 to 2
weeks, the dose is titrated to about 2.0 mg/kg. This process of
increasing the dose by about 0.5 mg/kg at each titration step and
the duration of treatment at each step of 1 to 2 weeks is continued
until the patient displays an adequate response to treatment, or a
maximal dose of 5 mg/kg is reached. Potential responses to
treatment could include loss of body fat, reduction in hypotonia,
an increase in the lean body mass to fat mass ratio, reduction in
hyperphagia, reduction in waist circumference, loss of weight,
reduction in temper outbursts and aggressive behavior, and
improvements in cardiovascular risk factors. Treatment with the
drug is chronic and may continue for life.
[0520] In a second example, a Smith-Magenis syndrome patient is
treated with a controlled release tablet formulation of diazoxide
choline. The initial dose is approximately 1.5 mg/kg administered
once daily. After the patient has been stably treated with 1.5
mg/kg for a period of 1 to 2 weeks, the dose is titrated to about
2.1 mg/kg. After the patient has been stably treated with 2.1 mg/kg
for a period of 1 to 2 weeks, the dose is titrated to about 2.7
mg/kg. This process of increasing the dose by about 0.6 mg/kg at
each titration step and the duration of treatment at each step of 1
to 2 weeks is continued until the patient displays an adequate
response to treatment, or a maximal dose of 5 mg/kg is reached.
Potential responses to treatment could include loss of body fat,
reduction in hypotonia, an increase in the lean body mass to fat
mass ratio, reduction in hyperphagia, reduction in waist
circumference, loss of weight, reduction in temper outbursts and
aggressive behavior and improvements in cardiovascular risk
factors. Treatment with the drug is chronic and may continue for
life.
[0521] In a third example, a Smith-Magenis syndrome patient is
treated with a controlled release tablet formulation of diazoxide
choline. The initial dose is approximately 1.5 mg/kg administered
once daily. After the patient has been stably treated with 1.5
mg/kg for a period of 1 to 2 weeks, the dose is titrated to about
2.2 mg/kg. After the patient has been stably treated with 2.2 mg/kg
for a period of 1 to 2 weeks, the dose is titrated to about 2.9
mg/kg. This process of increasing the dose by about 0.7 mg/kg at
each titration step and the duration of treatment at each step of 1
to 2 weeks is continued until the patient displays an adequate
response to treatment or a maximal dose of 5 mg/kg is reached. In
parallel, the patient may also be treated with beloranib. Potential
responses to treatment could include loss of body fat, reduction in
hypotonia, an increase in the lean body mass to fat mass ratio,
reduction in hyperphagia, reduction in waist circumference, loss of
weight, reduction in temper outbursts and aggressive behavior and
improvements in cardiovascular risk factors. Treatment with the
drug is chronic and may continue for life.
[0522] In a fourth example, a Smith-Magenis syndrome patient is
treated with a controlled release tablet formulation of diazoxide
choline. The initial dose is approximately 1.5 mg/kg administered
once daily. After the patient has been stably treated with 1.5
mg/kg for a period of 1 to 2 weeks, the dose is titrated to about
2.3 mg/kg. After the patient has been stably treated with 2.3 mg/kg
for a period of 1 to 2 weeks, the dose is titrated to about 3.0
mg/kg. This process of increasing the dose by about 0.8 mg/kg at
each titration step and the duration of treatment at each step of 1
to 2 weeks is continued until the patient displays an adequate
response to treatment, or a maximal dose of 5 mg/kg is reached. In
parallel, the patient may also be treated with an unacylated
ghrelin analog. Potential responses to treatment could include loss
of body fat, reduction in hypotonia, an increase in the lean body
mass to fat mass ratio, reductions in hyperphagia, reductions in
waist circumference, loss of weight, reductions in temper outbursts
and aggressive behavior and improvements in cardiovascular risk
factors. Treatment with the drug would be chronic and may continue
for life.
[0523] In a fifth example, a Smith-Magenis syndrome patient is
treated with a controlled release tablet formulation of diazoxide
choline. The initial dose is approximately 1.5 mg/kg administered
once daily. After the patient had been stably treated with 1.5
mg/kg for a period of 1 to 2 weeks, the dose would be titrated to
about 2.4 mg/kg. After the patient has been stably treated with 2.4
mg/kg for a period of 1 to 2 weeks, the dose is titrated to about
3.3 mg/kg. This process of increasing the dose by about 0.9 mg/kg
at each titration step and the duration of treatment at each step
of 1 to 2 weeks is continued until the patient displays an adequate
response to treatment, or a maximal dose of 5 mg/kg was reached. In
parallel, the patient may also be treated with an MC4 agonist.
Potential responses to treatment could include loss of body fat,
reduction in hypotonia, an increase in the lean body mass to fat
mass ratio, reductions in hyperphagia, reductions in waist
circumference, loss of weight, reductions in temper outbursts and
aggressive behavior and improvements in cardiovascular risk
factors. Treatment with the drug would be chronic and may continue
for life.
[0524] In a sixth example, a Smith-Magenis syndrome patient is
treated with a controlled release tablet formulation of diazoxide
choline. The initial dose is approximately 1.5 mg/kg administered
once daily. After the patient had been stably treated with 1.5
mg/kg for a period of 1 to 2 weeks, the dose is titrated to about
2.5 mg/kg. After the patient has been stably treated with 2.5 mg/kg
for a period of 1 to 2 weeks, the dose is titrated to about 3.5
mg/kg. This process of increasing the dose by about 1.0 mg/kg at
each titration step and the duration of treatment at each step of 1
to 2 weeks is continued until the patient displays an adequate
response to treatment, or a maximal dose of 5 mg/kg was reached. In
parallel, the patient may also be treated with an MC4 agonist.
Potential responses to treatment could include loss of body fat,
reduction in hypotonia, an increase in the lean body mass to fat
mass ratio, reductions in hyperphagia, reductions in waist
circumference, loss of weight, reductions in temper outbursts and
aggressive behavior and improvements in cardiovascular risk
factors. Treatment with the drug would be chronic and may continue
for life.
[0525] All patents and other references cited in the specification
are indicative of the level of skill of those skilled in the art to
which the invention pertains, and are incorporated by reference in
their entireties, including any tables and figures, to the same
extent as if each reference had been incorporated by reference in
its entirety individually.
[0526] One skilled in the art would readily appreciate that the
present invention is well adapted to obtain the ends and advantages
mentioned, as well as those inherent therein. The methods,
variances, and compositions described herein as presently
representative of preferred embodiments are exemplary and are not
intended as limitations on the scope. Changes therein and other
uses will occur to those skilled in the art, which are encompassed
within the spirit of the invention, are defined by the scope of the
claims.
[0527] Definitions provided herein are not intended to be limiting
from the meaning commonly understood by one of skill in the art
unless indicated otherwise.
[0528] The inventions illustratively described herein may suitably
be practiced in the absence of any element or elements, limitation
or limitations, not specifically disclosed herein. Thus, for
example, the terms "comprising", "including," containing", etc.
shall be read expansively and without limitation. Additionally, the
terms and expressions employed herein have been used as terms of
description and not of limitation, and there is no intention in the
use of such terms and expressions of excluding any equivalents of
the features shown and described or portions thereof, but it is
recognized that various modifications are possible within the scope
of the invention claimed. Thus, it should be understood that
although the present invention has been specifically disclosed by
preferred embodiments and optional features, modification and
variation of the inventions embodied therein herein disclosed may
be resorted to by those skilled in the art, and that such
modifications and variations are considered to be within the scope
of this invention.
[0529] The invention has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
invention. This includes the generic description of the invention
with a proviso or negative limitation removing any subject matter
from the genus, regardless of whether or not the excised material
is specifically recited herein.
[0530] Other embodiments are within the following claims. In
addition, where features or aspects of the invention are described
in terms of Markush groups, those skilled in the art will recognize
that the invention is also thereby described in terms of any
individual member or subgroup of members of the Markush group.
* * * * *