Note: Descriptions are shown in the official language in which they were submitted.
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
METHOD OF TREATING DIABETES
Field of the Invention
[0001] Methods are provided for treating diabetes, lowering plasma level of
HbAlc, in
a diabetic, pre-diabetic, or non-diabetic patient suffering from at least one
cardiovascular disease comprising administering ranolazine to these patients.
Background
[0002] Diabetes mellitus is a disease characterized by hyperglycemia; altered
metabolism of lipids, carbohydrates and proteins; and an increased risk of
complications from vascular disease. Diabetes is an increasing public health
problem,
as it is associated with both increasing age and obesity.
[0003] There are two major types of diabetes mellitus: 1) Type I, also known
as insulin
dependent diabetes (IDDM) and 2) Type II, also known as insulin independent or
non-
insulin dependent diabetes (NIDDM). Both types of diabetes mellitus are due to
insufficient amounts of circulating insulin and a decrease in the response of
peripheral
tissue to insulin.
[0004] Type I diabetes results from the body's failure to produce insulin, the
hormone
that "unlocks" the cells of the body, allowing glucose to enter and fuel them.
The
complications of Type I diabetes include heart disease and stroke; retinopathy
(eye
disease); kidney disease (nephropathy); neuropathy (nerve damage); as well as
maintenance of good skin, foot and oral health.
[0005] Type II diabetes results from the body's inability to either produce
enough
insulin or the cells inability to use the insulin that is naturally produced
by the body.
The condition where the body is not able to optimally use insulin is called
insulin
resistance. Type II diabetes is often accompanied by high blood pressure and
this may
contribute to heart disease. In patients with type II diabetes mellitus,
stress, infection,
and medications (such as corticosteroids) can also lead to severely elevated
blood sugar
levels. Accompanied by dehydration, severe blood sugar elevation in patients
with type
II diabetes can lead to an increase in blood osmolality (hyperosmolar state).
This
condition can lead to coma.
[0006] Insulin lowers the concentration of glucose in the blood by stimulating
the
uptake and metabolism of glucose by muscle and adipose tissue. Insulin
stimulates the
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
storage of glucose in the liver as glycogen, and in adipose tissue as
triglycerides.
Insulin also promotes the utilization of glucose in muscle for energy. Thus,
insufficient
insulin levels in the blood, or decreased sensitivity to insulin, gives rise
to excessively
high levels of glucose and triglycerides in the blood.
[0007] The early symptoms of untreated diabetes mellitus are related to
elevated blood
sugar levels, and loss of glucose in the urine. High amounts of glucose in the
urine can
cause increased urine output and lead to dehydration. Dehydration causes
increased
thirst and water consumption. The inability to utilize glucose energy
eventually leads
to weight loss despite an increase in appetite. Some untreated diabetes
patients also
complain of fatigue, nausea, and vomiting. Patients with diabetes are prone to
developing infections of the bladder, skin, and vaginal areas. Fluctuations in
blood
glucose levels can lead to blurred vision. Extremely elevated glucose levels
can lead to
lethargy and coma (diabetic coma).
[0008] People with glucose levels between normal and diabetic have impaired
glucose
tolerance (IGT). This condition is also called pre-diabetes or insulin
resistance
syndrome. People with IGT do not have diabetes, but rather have blood glucose
levels
that are higher than normal but not yet high enough to be diagnosed as
diabetes. Their
bodies make more and more insulin, but because the tissues don't respond to
it, their
bodies can't use sugar properly. Recent studies have shown that IGT itself may
be a
risk factor for the development of heart disease. It is estimated that people
with pre-
diabetes have a 1.5-fold risk of cardiovascular disease compared to people
with normal
blood glucose. People with diabetes have a 2- to 4-fold increased risk of
cardiovascular
disease.
[0009] High blood levels of glucose and triglycerides cause the thickening of
capillary
basement membrane, which results in the progressive narrowing of vessel
lumina. The
vasculopathogies give rise to conditions such as diabetic retinopathy, which
may result
in blindness, coronary heart disease, intercapillary glomerulosclerois,
neuropathy, and
ulceration and gangrene of the extremities.
[0010] The toxic effects of excess plasma levels of glucose include the
glycosylation of
cells and tissues. Glycosylated products accumulate in tissues and may
eventually form
cross-linked proteins, which cross-linked proteins are termed advanced
glycosylation
end products. It is possible that non-enzymatic glycosylation is directly
responsible for
expansion of the vascular matrix and vascular complications of diabetes. For
example,
glycosylation of collagen results in excessive cross-linking, resulting in
atherosclerotic
2
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
vessels. Also, the uptake of glycosylated proteins by macrophages stimulates
the
secretion of pro-inflammatory cytokines by these cells. The cytokines activate
or
induce degradative and proliferative cascades in mesenchymal and endothelial
cells
respectively.
[0011] The glycosylation of hemoglobin provides a convenient method to
determine an
integrated index of the glycemic state. The level of glycosylated proteins
reflects the
level of glucose over a period of time and is the basis of an assay referred
to as the
hemoglobulin Al (HbAlc) assay
[0012] HbAlc reflects a weighted average of blood glucose levels during the
previous
120 days; plasma glucose in the previous 30 days contributes about 50% to the
final
result in an HbAlc assay. The test for Alc (also known as HbAlc,
glycohemoglobin,
or glycated hemoglobin) indicates how well diabetes has been controlled over
the last
few months. The closer Alc is to 6%, the better the control of diabetes. For
every 30
mg/dl increase in Alc blood glucose, there is a 1% increase in Alc, and the
risk of
complications increases.
[0013] Another explanation for the toxic effects of hyperglycemia includes
sorbitol
formation. Intracellular glucose is reduced to its corresponding sugar
alcohol, sorbitol,
by the enzyme aldose reductase; the rate of production of sorbitol is
determined by the
ambient glucose concentration. Thus, tissues such as lens, retina, arterial
wall and
schwann cells of peripheral nerves have high concentrations of sorbitol.
[0014] Hyperglycemia also impairs the function of neural tissues because
glucose
competes with myoinositol resulting in reduction of cellular concentrations
and,
consequently, altered nerve function and neuropathy.
[0015] Increased triglyceride levels are also a consequence of insulin
deficiency. High
triglyceride levels are also associated with vascular disease.
[0016] Thus, controlling blood glucose and triglyceride levels is a desirable
therapeutic
goal. A number of oral antihyperglycemic agents are known. Medications that
increase the insulin output by the pancreas include sulfonylureas (including
chlorpropamide [Orinase ], tolbutamide [Tolinase ], glyburide [Micronase ],
glipizide [Glucotrol ], and glimepiride [Amaryl ]) and meglitinides (including
reparglinide [Prandin ] and nateglinide [Starlix ]). Medications that decrease
the
amount of glucose produced by the liver include biguanides (including
metformin
[Glucophage ]. Medications that increase the sensitivity of cells to insulin
include
thazolidinediones (including troglitazone [Resulin ], pioglitazone [Actos ]
and
3
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
rosiglitazone [Avandia ]). Medications that decrease the absorption of
carbohydrates
from the intestine include alpha glucosidase inhibitors (including acarbose
[Precose ]
and miglitol [Glyset ]). Actos and Avandia can change the cholesterol
patterns in
diabetics. HDL (or good cholesterol) increases on these medications. Precose
works
on the intestine; its effects are additive to diabetic medications that work
at other sites,
such as sulfonylureas. ACE inhibitors can be used to control high blood
pressure, treat
heart failure, and prevent kidney damage in people with hypertension or
diabetes. ACE
inhibitors or combination products of an ACE inhibitor and a diuretic, such as
hydrochlorothazide, are marketed. However, none of these treatments is ideal.
[0017] Blood pressure control can reduce cardiovascular disease (for example,
myocardial infarction and stroke) by approximately 33% to 50% and can reduce
microvascular disease (eye, kidney, and nerve disease) by approximately 33%.
The
Center for Disease Control has found that for every 10 millimeters of mercury
(mm Hg)
reduction in systolic blood pressure, the risk for any complication related to
diabetes is
reduced by 12%. Improved control of cholesterol and lipids (for example HDL,
LDL,
and triglycerides) can reduce cardiovascular complications by 20% to 50%.
[0018] Total cholesterol should be less than 200 mg/dl. Target levels for high
density
lipoprotein (HDL or "good" cholesterol) are above 45 mg/dl for men and above
55
mg/dl for women, while low density lipoprotein (LDL or "bad" cholesterol)
should be
kept below 100 mg/dl. Target triglyceride levels for women and men are less
than 150
mg/dl.
[0019] Approximately 50% of patients with diabetes develop some degree of
diabetic
retinopathy after 10 years of diabetes, and 80% of diabetics have retinopathy
after 15
years.
[0020] In a study (the DCCT study) conducted by the National Institute of
Diabetes
and Disgestive and Kidney Diseases (NIDDK) it was shown that keeping blood
glucose
levels as close to normal as possible slows the onset and progression of eye,
kidney,
and nerve diseases caused by diabetes.
[0021] In the Diabetes Prevention Program (DPP) clinical trial type 2
diabetics were
studied. The DPP study found that over the 3 years of the study, diet and
exercise
sharply reduced the chances that a person with IGT would develop diabetes.
Administration of metformin (Glucophage ) also reduced risk, although less
dramatically.
4
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0022] The DCCT study showed a correlation between HbAlc and the mean blood
glucose. The DPP study showed that HbAlc is strongly correlated with adverse
outcome risk.
[0023] In a series of reports from the American Heart Association's Prevention
Conference VI: Diabetes and Cardiovascular Disease it was reported that about
two-
thirds of people with diabetes eventually die of heart or blood vessel
disease. Studies
also showed that the increase in cardiovascular disease risk associated with
diabetes can
be lessened by controlling individual risk factors such as glucose level,
obesity, high
cholesterol, and high blood pressure.
[0024] It is important for a person suffering from diabetes to reduce the risk
of
complications such as cardiovascular disease, retinopathy, nephropathy, and
neuropathy. It is also important for diabetics to reduce total cholesterol and
triglyceride
levels to reduce cardiovascular complications. Reduction of these possible
complication risks is also important for a person suffering from IGT (a pre-
diabetic).
[0025] Thus, if HbAlc and blood glucose levels can be controlled, the risk of
complications such as cardiovascular disease, retinopathy, nephropathy, and
neuropathy can be reduced or their onset delayed. If total cholesterol and
triglyceride
levels can be reduced, then cardiovascular complications can be reduced.
[0026] U.S. Patent No. 4,567,264, the specification of which is incorporated
herein by
reference in its entirety, discloses ranolazine, ( )-N-(2,6-dimethylphenyl)-4-
[2-
hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, and its
pharmaceutically acceptable salts, and their use in the treatment of
cardiovascular
diseases, including arrhythmias, variant and exercise-induced angina, and
myocardial
infarction. In its dihydrochloride salt form, ranolazine is represented by the
formula:
N N
_
CH3 NH_~_
\_/ -)-\
- O 2HC1 OH O
\ / CH3 \ /
dH3C0
[0027] This patent also discloses intravenous (IV) formulations of
dihydrochloride
ranolazine further comprising propylene glycol, polyethylene glyco1400, Tween
80 and
0.9% saline.
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0028] U.S. Patent No. 5,506,229, which is incorporated herein by reference in
its
entirety, discloses the use of ranolazine and its pharmaceutically acceptable
salts and
esters for the treatment of tissues experiencing a physical or chemical
insult, including
cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or
brain tissue,
and for use in transplants. Oral and parenteral formulations are disclosed,
including
controlled release formulations. In particular, Example 7D of U.S. Patent No.
5,506,229 describes a controlled release formulation in capsule form
comprising
microspheres of ranolazine and microcrystalline cellulose coated with release
controlling polymers. This patent also discloses IV ranolazine formulations
which at
the low end comprise 5 mg ranolazine per milliliter of an IV solution
containing about
5% by weight dextrose. And at the high end, there is disclosed an IV solution
containing 200 mg ranolazine per milliliter of an IV solution containing about
4% by
weight dextrose.
[0029] The presently preferred route of administration for ranolazine and its
pharmaceutically acceptable salts and esters is oral. A typical oral dosage
form is a
compressed tablet, a hard gelatin capsule filled with a powder mix or
granulate, or a soft
gelatin capsule (softgel) filled with a solution or suspension. U.S. Patent
No.
5,472,707, the specification of which is incorporated herein by reference in
its entirety,
discloses a high-dose oral formulation employing supercooled liquid ranolazine
as a fill
solution for a hard gelatin capsule or softgel.
[0030] U.S. Patent No. 6,503,911, the specification of which is incorporated
herein by
reference in its entirety, discloses sustained release formulations that
overcome the
problem of affording a satisfactory plasma level of ranolazine while the
formulation
travels through both an acidic environment in the stomach and a more basic
environment through the intestine, and has proven to be very effective in
providing the
plasma levels that are necessary for the treatment of angina and other
cardiovascular
diseases.
[0031] U.S. Patent No. 6,852,724, the specification of which is incorporated
herein by
reference in its entirety, discloses methods of treating cardiovascular
diseases,
including arrhythmias variant and exercise-induced angina and myocardial
infarction.
[0032] U.S. Patent Application Publication Number 2006/0177502, the
specification of
which is incorporated herein by reference in its entirety, discloses oral
sustained release
6
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
dosage forms in which the ranolazine is present in 35-50%, preferably 40-45%
ranolazine. In one embodiment the ranolazine sustained release formulations of
the
invention include a pH dependent binder; a pH independent binder; and one or
more
pharmaceutically acceptable excipients. Suitable pH dependent binders include,
but are
not limited to, a methacrylic acid copolymer, for example Eudragit (Eudragit
L100-
55, pseudolatex of Eudragit L100-55, and the like) partially neutralized with
a strong
base, for example, sodium hydroxide, potassium hydroxide, or ammonium
hydroxide,
in a quantity sufficient to neutralize the methacrylic acid copolymer to an
extent of
about 1-20%, for example about 3-6%. Suitable pH independent binders include,
but
are not limited to, hydroxypropylmethylcellulose (HPMC), for example Methocel
E10M Premium CR grade HPMC or Methocel E4M Premium HPMC. Suitable
pharmaceutically acceptable excipients include magnesium stearate and
microcrystalline cellulose (Avicel pH101).
[0033] In acute or emergency situations in which a patient either is or
recently has
experienced an acute cardiovascular disease event there is a need to initially
and rapidly
stabilize the patient. Once the patient has been stabilized there is a need to
maintain the
patient's stability by providing treatment over an extended period of time.
[0034] In diabetic, pre-diabetic, or non-diabetic coronary patients suffering
from
cardiovascular diseases there is a need to reduce the HbAlc level while
treating the
cardiovascular disease.
[0035] There is a need for a method for treating diabetic, pre-diabetic, or
non-diabetic
coronary patients suffering from an acute cardiovascular diseases comprising
administering ranolazine in an intravenous (IV) formulation that provides
therapeutically effective plasma concentrations of ranolazine in humans to
treat the
acute cardiovascular disease while reducing the HbAlc level of the patient.
[0036] There is also a need for a method for treating diabetic, pre-diabetic,
or non-
diabetic coronary patients suffering from cardiovascular diseases comprising
administering ranolazine in an oral formulation that provides therapeutically
effective
plasma concentrations of ranolazine in humans to treat the cardiovascular
disease while
reducing the HbAlc level of the patient.
[0037] During angina clinical trials using ranolazine, it was surprisingly
discovered
that treatment of diabetic angina patients with ranolazine was not only
effective in
treating angina, but also reduced hemoglobulin A1 (HbAlc) levels and, over the
long
7
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
term, reduced triglyceride levels. Ranolazine was also found to reduce
triglyceride
levels in non-diabetic patients. Ranolazine was also found to lower glucose
plasma
levels and, over the long term, total cholesterol levels, while increasing HDL
cholesterol levels. Thus, ranolazine provides a method of treating diabetes
pre-
diabetes, or the non-diabetes condition by reducing the levels of potentially
toxic
metabolites in blood and/or complications associated with diabetes. Ranolazine
also
can reduce the number of medications necessary for a patient with both
cardiovascular
problems and diabetes or pre-diabetes.
SUMMARY OF THE INVENTION
[0038] It is an object of this invention to provide an effective method of
lowering the
plasma level of HbAlc in a diabetic, pre-diabetic, or non-diabetic patient
suffering
from at least one cardiovascular disease while minimizing undesirable side
effects.
[0039] Accordingly, in a first aspect, the invention relates to a method of
lowering the
plasma level of HbAlc in a diabetic, pre-diabetic, or non-diabetic patient
suffering
from at least one cardiovascular disease, comprising administration of a
therapeutically
effective amount of a compound of Formula I:
9 10
R R R12 R11 R1 Rz
Ra / \ / \N I
3
R
- OH \ / O
R7 R6 ~J R5 4
Formula I
wherein:
[0040] R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl,
lower
alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl,
lower alkyl
sulfonyl, or N-optionally substituted alkylamido, provided that when Ri is
methyl, R4 is
not methyl;
or R2 and R3 together form -OCH2 0--;
R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl,
aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo,
lower
alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl
amino; or
R6 and R7 together form -CH=CH-CH=CH--; or
8
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
R7 and R8 together form -O-CHz 0--;
Rii and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof
[0041] The compounds of Formula I are disclosed in more detail in U.S. Patent
No.
U.S. 4,567,264, the complete disclosure of which is hereby incorporated by
reference.
A preferred compound of this invention is ranolazine, which is named N-(2,6-
dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-
piperazineacetamide,
as a racemic mixture, or an isomer thereof, or a pharmaceutically acceptable
salt
thereof.
[0042] A second aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, wherein the cardiovascular disease is angina.
[0043] A third aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, wherein the cardiovascular disease is chronic angina.
[0044] A fourth aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administering a therapeutically effective
amount of
ranolazine.
[0045] A fifth aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administration of a therapeutically
effective amount
of a compound of Formula I:
9 10
R R R12 R11 R1 Rz
Ra / \ / \N I
3
R
- OH O
R7 R6 R5 4
Formula I
wherein:
[0046] R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl,
lower
alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl,
lower alkyl
9
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
sulfonyl, or N-optionally substituted alkylamido, provided that when Ri is
methyl, R4 is
not methyl;
or R2 and R3 together form -OCH2 0--;
R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl,
aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo,
lower
alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl
amino; or
R6 and R7 together form -CH=CH-CH=CH--; or
R7 and R8 together form -0-CH2 0--;
Rii and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof;
to a mammal in need thereof, wherein the compound of Formula I is administered
as an
immediate release formulation.
[0047] A sixth aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administration of a therapeutically
effective amount
of a compound of Formula I:
9 10
R R R12 R11 R1 Rz
Ra / \ / \N I
3
R
- OH O
R7 R6 R5 4
Formula I
wherein:
[0048] R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl,
lower
alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl,
lower alkyl
sulfonyl, or N-optionally substituted alkylamido, provided that when Ri is
methyl, R4 is
not methyl;
or R2 and R3 together form -OCHz 0--;
R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl,
aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo,
lower
alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl
amino; or
R6 and R7 together form -CH=CH-CH=CH--; or
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
R7 and R8 together form -O-CHz 0--;
Rii and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt or ester thereof, or an isomer thereof;
to a mammal in need thereof, wherein the compound of Formula I is administered
as a
sustained release formulation.
[0049] A seventh aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administration of a therapeutically
effective amount
of a compound of Formula I to a mammal in need thereof, wherein the compound
of
Formula I is administered in a formulation that has both immediate release and
sustained release aspects.
[0050] An eighth aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administration of a therapeutically
effective amount
of a sustained release formulation comprising a compound of Formula I to a
mammal in
need thereof, wherein the sustained release formulation provides a plasma
level of
ranolazine between 550 and 7500 ng base/ml over a 24 hour period.
[0051] A ninth aspect of the invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administering a compound of Formula I
wherein the
dosage is from about 250 mg bid to about 2000 mg bid to a mammal.
[0052] A tenth aspect of this invention is a method of lowering the plasma
level of
HbAlc in a diabetic, pre-diabetic, or non-diabetic patient suffering from at
least one
cardiovascular disease, comprising administering from about 250 mg bid to
about 2000
mg bid of ranolazine.
[0053] An eleventh aspect of this invention is a method of reducing negative
consequences of diabetes comprising administration of ranolazine.
[0054] A twelfth aspect of this invention is a method of delaying or slowing
the
development of diabetes comprising administration of ranolazine.
[0055] A thirteenth aspect of this invention is a method of delaying the
initiation of
insulin treatment comprising administration of ranolazine.
[0056] A fourteenth aspect of this invention is a method of reducing HbAlc
levels in a
patient without leading to hypoglycemia comprising administration of
ranolazine.
11
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0057] A fifteenth aspect of this invention is a method of delaying or slowing
the
development of worsening hyperglycemia in a diabetic, pre-diabetic, or non-
diabetic
patient suffering from at least one cardiovascular disease, comprising
administration of
ranolazine.
[0058] A sixteenth aspect of this invention is a method of reducing or slowing
the
development of hyperglycemia in a diabetic, pre-diabetic, or non-diabetic
patient
suffering from at least one cardiovascular disease, comprising administration
of
ranolazine.
BRIEF DESCRIPTION OF THE FIQURES
[0059] Figure 1. CV Death/MI/Severe recurrent ischemia
[0060] Figure 2. Effect of Ranolazine on HbAlc Levels.
[0061] Figure 3. CARISA Primary Endpoint: Exercise Duration at Trough. This
figure shows changes from baseline (in sec) for diabetics and non-diabetics on
placebo,
750 mg ranolazine bid, or 1000 mg ranolazine bid.
[0062] Figure 4. CARISA: Exercise Duration at Peak. This figure shows changes
from baseline (in sec) for diabetics and non-diabetics on placebo, 750 mg
ranolazine
bid, or 1000 mg ranolazine bid.
[0063] Figure 5. CARISA: Exercise Time to Onset of Angina. This figure shows
changes from baseline (in sec) in trough and peak for diabetics and non-
diabetics on
placebo, 750 mg ranolazine bid, or 1000 mg ranolazine bid.
[0064] Figure 6. CARISA: Change from Baseline in HbAlc (all diabetic
patients). This figure shows percentage of HbAlc for diabetics on placebo, 750
mg
ranolazine bid, or 1000 mg ranolazine bid at baseline and at last study value.
[0065] Figure 7. CARISA: Change from Baseline in HbAlc (Dependent vs Non-
insulin Dependent Diabetic Patients. This figure shows percentage of HbAlc for
both
12
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
insulin dependent and non-insulin dependent diabetics on placebo, 750 mg
ranolazine
bid, or 1000 mg ranolazine bid at baseline and at last study value.
[0066] Figure 8: Change in HbAlc (%). Figure 8A shows the percentage change
in HbAla in patients diagnosed with diabetes mellitus before or at the start
of
randomization for this trial versus the months (16) of follow-up. Figure 8A
shows
M4 M8 M16
Placebo N=770 N=598 N=122
Ranolazine N=707 N=535 N=1 12
P-value <0.001 <0.001 =0.13
[0067] Figure 8B shows the percentage change in HbAlc in patients that were
either
pre-diabetic or non-diabetic at the start of randomization for this trial (had
not been
diagnosed as diabetic before the start of this trial) versus the months (16)
of follow-up.
Figure 8B shows
M4 M8 M16
Placebo N=1428 N=1113 N=260
Ranolazine N=1401 N=1113 N=266
P-value <0.001 =0.002 =0.025
DETAILED DESCRIPTION OF THE INVENTION
[0068] The invention provides a method of lowering the plasma level of HbAlc
in a
diabetic, pre-diabetic, or non-diabetic patient suffering from at least one
cardiovascular
disease, comprising administration of a compound of Formula I.
[0069] Diabetes, as defined herein, is a disease state characterized by
hyperglycemia;
altered metabolism of lipids, carbohydrates, and proteins; and an increased
risk of
complications from vascular disease.
[0070] Pre-diabetes, as defined herein, includes people with glucose levels
between
normal and diabetic have impaired glucose tolerance (IGT). This condition is
also
called pre-diabetes or insulin resistance syndrome. People with IGT do not
have
diabetes, but rather have blood glucose levels that are higher than normal but
not yet
high enough to be diagnosed as diabetes. Their bodies make more and more
insulin,
but because the tissues don't respond to it, their bodies can't use sugar
properly.
Glycemic control is the regulation of blood glucose levels
Hemoglobin undergoes glycosylation on its amino terminal valine residue to
form the glucosyl valine adduct of hemoglobin (HbAlc). The toxic effects of
13
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
hyperglycemia may be the result of accumulation of such nonenzymatically
glycosylated products. The covalent reaction of glucose with hemoglobin also
provides
a convenient method to determine an integrated index of the glycemic state.
For
example, the half-life of the modified hemoglobin is equal to that of the
erythrocyte
(about 120 days). Since the amount of glycosylated protein is proportional to
the
glucose concentration and the time of exposure of the protein to glucose, the
concentration of HbAlc in the circulation reflects the glycemic state over an
extended
period (4 to 12 weeks) prior to sampling. Thus, a rise in HbAlc from 5% to 10%
suggests a prolonged doubling of the mean blood glucose concentration
[0071] With respect to the compound of Formula I, the following words and
phrases
are generally intended to have the meanings as set forth below, except to the
extent that
the context in which they are used indicates otherwise.
"Aminocarbonylmethyl" refers to a group having the following structure:
0
A
NHz
where A represents the point of attachment.
"Halo" or "halogen" refers to fluoro, chloro, bromo or iodo.
"Lower acyl" refers to a group having the following structure:
O
R A
where R. is lower alkyl as is defined herein, and A represents the point of
attachment,
and includes such groups as acetyl, propanoyl, n-butanoyl and the like.
"Lower alkyl" refers to an unbranched saturated hydrocarbon chain of 1-4
carbons, such as methyl, ethyl, n-propyl, and n-butyl.
"Lower alkoxy" refers to a group --OR wherein R is lower alkyl as herein
defined.
"Lower alkylthio" refers to a group --SR wherein R is lower alkyl as herein
defined.
"Lower alkyl sulfinyl" refers to a group of the formula:
0
11
R R14 \A
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
wherein R is lower alkyl as herein defined, and A represents the point of
attachment.
"Lower alkyl sulfonyl" refers to a group of the formula:
0
R/II\A
wherein R is lower alkyl as herein defined., and A represents the point of
attachment.
[0072] "N-Optionally substituted alkylamido" refers to a group having the
following
structure:
0
R' N A
R
wherein R is independently hydrogen or lower alkyl and R' is lower alkyl as
defined
herein, and A represents the point of attachment.
[0073] The term "compound of Formula I" is intended to encompass the compounds
of
the invention as disclosed, and the pharmaceutically acceptable salts,
pharmaceutically
acceptable esters, and prodrugs of such compounds.
[0074] "Isomers" refers to compounds having the same atomic mass and atomic
number but differing in one or more physical or chemical properties. All
isomers of the
compounds of Formula I, including the R- and S- enantiomers are within the
scope of
the invention.
[0075] In many cases, the compounds of this invention are capable of forming
acid
and/or base salts by virtue of the presence of amino and/or carboxyl groups or
groups
similar thereto. The term "pharmaceutically acceptable salt" refers to salts
that retain
the biological effectiveness and properties of the compounds of Formula I, and
which
are not biologically or otherwise undesirable. Pharmaceutically acceptable
base
addition salts can be prepared from inorganic and organic bases. Salts derived
from
inorganic bases, include by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic bases
include,
but are not limited to, salts of primary, secondary and tertiary amines, such
as alkyl
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
amines, dialkyl amines, trialkyl amines, substituted alkyl amines,
di(substituted alkyl)
amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,
trialkenyl
amines, substituted alkenyl amines, di(substituted alkenyl) amines,
tri(substituted
alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl)
amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted
cycloalkyl
amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)
amines,
substituted cycloalkenyl amines, disubstituted cycloalkenyl amine,
trisubstituted
cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl
amines,
diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic
amines,
triheterocyclic amines, mixed di- and tri-amines where at least two of the
substituents
on the amine are different and are selected from the group consisting of
alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and
the like. Also
included are amines where the two or three substituents, together with the
amino
nitrogen, form a heterocyclic or heteroaryl group.
[0076] Specific examples of suitable amines include, by way of example only,
isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-
propyl)
amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine,
histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine,
morpholine, N-ethylpiperidine, and the like.
[0077] Pharmaceutically acceptable acid addition salts may be prepared from
inorganic
and organic acids. Salts derived from inorganic acids include hydrochloric
acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Salts derived
from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic
acid,
oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid,
ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0078] As used herein, "pharmaceutically acceptable carrier" includes any and
all
solvents, dispersion media, coatings, antibacterial and antifungal agents,
isotonic and
absorption delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except insofar as
any
conventional media or agent is incompatible with the active ingredient, its
use in the
therapeutic compositions is contemplated. Supplementary active ingredients can
also
16
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
be incorporated into the compositions.
[0079] The term "therapeutically effective amount" refers to that amount of a
compound of Formula I that is sufficient to effect treatment, as defined
below, when
administered to a mammal in need of such treatment. The therapeutically
effective
amount will vary depending upon the subject and disease condition being
treated, the
weight and age of the subject, the severity of the disease condition, the
manner of
administration and the like, which can readily be determined by one of
ordinary skill in
the art.
[0080] The term "treatment" or "treating" means any treatment of a disease in
a
mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the
disease
not to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical
symptoms; and/or
(iii) relieving the disease, that is, causing the regression of clinical
symptoms.
The "patient" is a mammal, preferably a human.
[0081] Physiologically acceptable pH" refers to the pH of an intravenous
solution
which is compatible for delivery into a human patient. Preferably,
physiologically
acceptable pH's range from about 4 to about 8.5 and preferably from about 4 to
7.
Without being limited by any theory, the use of intravenous solutions having a
pH of
about 4 to 6 are deemed physiologically acceptable as the large volume of
blood in the
body effectively buffers these intravenous solutions.
[0082] "Coronary diseases" or "cardiovascular diseases" refer to diseases of
the
cardiovasculature arising from any one or more than one of, for example, heart
failure,
including congestive heart failure, acute heart failure, ischemia, recurrent
ischemia,
myocardial infarction, arrhythmias, angina (including exercise-induced angina,
variant
angina, stable angina, unstable angina), acute coronary syndrome, diabetes,
and
intermittent claudication. The treatment of such disease states is disclosed
in various
U.S. patents and patent applications, including U.S. Patent Nos. 6,503,911 and
6,528,511, U.S. Patent Application Serial Nos. 2003/0220344 and 2004/0063717,
the
complete disclosures of which are hereby incorporated by reference.
[0083] "An acute coronary disease event" refers to any condition relating to
one or
more coronary diseases which has/have manifested itself/themselves or has
deteriorated
17
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
to the point where the patient seeks medical intervention typically but not
necessarily in
an emergency situation.
[0084] "Acute coronary syndrome" or "ACS" refers to a range of acute
myocardial
ischemic states. It encompasses unstable angina and non-ST-segment elevation
myocardial infarction (UA/NSTEMI), and ST segment elevation myocardial
infarction
(STEMI). STEMI refers to a complete occlusion by thrombus. In a preferred
embodiment, ACS refers to those patients with a non-ST elevation acute
coronary
syndrome (NSTEACS). NSTEACS refers to a partial occlusion by the thrombus.
NSTEACS is further defined as chest discomfort or anginal equivalent occurring
at
rest, lasting _10 minutes, and consistent with myocardial ischemia, and the
presence of
ischemic symptoms (_5 minutes) at rest within 48 hours of admittance which may
include index episode, and having at least one of the following indicators of
moderate -
high risk:
= Elevated cardiac troponin (above local MI limit) or CK-MB (>ULN)
= ST-depression (horizontal or down-sloping) _ 0.1 mV
= Diabetes mellitus (requiring insulin or oral therapy)
= A Risk Score of _ 3 wherein one point is assigned for each of the following
variables and a total score calculated as the arithmetic sum:
o Age _ 65 years;
o Known CAD (prior MI, CABG, PCI or angiographic
stenosis _50%);
o Three or more cardiac risk factors (DM, elevated
cholesterol, hypertension, family history);
o More than one episode of ischemic discomfort at rest in
o the prior 24 hours;
o Chronic aspirin use in the 7 days preceding onset of
symptoms;
o ST segment depression _ 0.05 mV; and
o Elevated cardiac troponin or CK-MB.
[0085] These risk indicators are also referred to as TIMI (thrombolysis in
myocardial
ischemia) risk factors and are further discussed in Chase, et al., Annals of
Emergency
Medicine, 48(3):252-259 (2006); Sadanandan, et al., J Am Coll Cardiol.,
44(4):799-803
18
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
(2004); and Conway, et al., Heart, 92:1333-1334 (2006), each of which is
incorporated
by reference in its entirety herein.
[0086] "Unstable angina" or "UA" refers to a clinical syndrome between stable
angina
and acute myocardial infarction. This definition encompasses many patients
presenting
with varying histories and reflects the complex pathophysiological mechanisms
operating at different times and with different outcomes. Three main
presentations
have been described - angina at rest, new onset angina, and increasing angina.
[0087] "ECG" refers to an electrocardiogram.
[0088] "Cardiovascular intervention" or "coronary intervention" refers to any
invasive
procedure to treat a coronary disease including, but not limited to,
"percutaneous
coronary intervention" or PCI. It is contemplated that PCI encompasses a
number of
procedures used to treat patients with diseases of the heart. Examples of PCI
include,
but are not limited to, PTCA (percutaneous transluminal coronary angioplasty),
implantation of stents, pacemakers, and other coronary devices, CABG (coronary
artery
bypass graft surgery) and the like.
[0089] "Optional" and "optionally" mean that the subsequently described event
or
circumstance may or may not occur, and that the description includes instances
where
the event or circumstance occurs and instances in which it does not. For
example,
"optional pharmaceutical excipients" indicates that a formulation so described
may or
may not include pharmaceutical excipients other than those specifically stated
to be
present, and that the formulation so described includes instances in which the
optional
excipients are present and instances in which they are not.
[0090] "Emergency" refers to an acute situation in which the patient is
initially seen by
medical personnel. Emergency situations can include, but are not limited to,
medical
facilities such as hospitals or clinics, emergency rooms at medical facilities
such as
hospitals or clinics, and emergency situations which involve police and/or
medical
personnel such as firemen, ambulance attendants, or other medically trained
persons.
[0091] "Stabilized" or "stable" refers to a condition in which a patient is
not
considered to be in immediate risk of morbidity.
[0092] "Immediate release" ("IR") refers to formulations or dosage units that
rapidly
dissolve in vitro and are intended to be completely dissolved and absorbed in
the stomach
19
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
or upper gastrointestinal tract. Conventionally, such formulations release at
least 90%
of the active ingredient within 30 minutes of administration.
[0093] "Sustained release" ("SR") refers to formulations or dosage units used
herein
that are slowly and continuously dissolved and absorbed in the stomach and
gastrointestinal tract over a period of about six hours or more. Preferred
sustained
release formulations are those exhibiting plasma concentrations of ranolazine
suitable
for no more than twice daily administration with two or less tablets per
dosing as
described below.
[0094] "Intravenous (IV) infusion" or "intravenous administration" refers to
solutions
or dosage units used herein that are provided to the patient by intravenous
route. Such
IV infusions can be provided to the patient until for up to about 96 hours in
order to
stabilize the patient's cardiovascular condition. The method and timing for
delivery of
an IV infusion is within the skill of the attending medically trained person.
[0095] "Renal insufficiency" refers to when a patient's kidneys no longer have
enough
kidney function to maintain a normal state of health. Renal insufficiency
includes both
acute and chronic renal failure, including end-stage renal disease (ESRD).
Methods of this Invention
[0096] As noted previously, in one aspect, this invention provides for a
method for
treating a diabetic, pre-diabetic, or non-diabetic patient suffering from an
acute
cardiovascular disease event. In a further embodiment of this aspect, the
diabetic, pre-
diabetic, or non-diabetic patient suffering from acute cardiovascular disease
event
exhibits one or more conditions associated with non-ST elevation acute
coronary
syndrome.
[0097] Patients presenting themselves with an acute coronary disease event
include, but
are not limited to, those who are being treated for one or more of the
following: angina
including stable angina, unstable angina (UA), exercised-induced angina,
variant
angina, arrhythmias, intermittent claudication, myocardial infarction
including non-
STE myocardial infarction (NSTEMI), heart failure including congestive (or
chronic)
heart failure, acute heart failure, or recurrent ischemia.
[0098] The methods of this aspect of the invention are preferably achieved by
administering to the presenting patient an IV solution comprising a selected
concentration of ranolazine. Heretofore, the art provided IV solutions
comprising
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
ranolazine which comprised low concentrations of ranolazine (see, e.g., Kluge
et al.,
U.S. Patent No. 4,567,264 where Example 11 of that patent describes using 1.4
mg of
ranolazine per mL in an IV solution comprising significant amounts of both
propylene
glycol (20 g/100 mL) and polyethylene glycol (20 g/100 mL)). Propylene glycol
is a
viscous liquid as is polyethylene glycol (see, e.g., the Merck Index, 12th
Ed., 1996).
The increased viscosity resulting from the use of such IV solutions makes the
rapid
delivery of ranolazine to the patient suffering from an acute cardiovascular
disease
event more cumbersome and requires that a significant amount of propylene
glycol and
polyethylene glycol be co-administered.
[0099] Alternatively, the art provided IV solutions comprising ranolazine
which
comprised either high or very high concentrations of ranolazine (either 5 mg/
mL or
200 mg/mL) relative to that employed in the IV solutions used herein. See,
e.g., Dow,
et al., U.S. Patent No. 5,506,229. In an acute cardiovascular disease event
where the
patient is suffering from or at risk of suffering from renal insufficiency,
the use of such
concentrations of ranolazine can result in higher ranolazine plasma levels.
Accordingly, the use of such concentrations is contraindicated for treating
patients
presenting with an acute cardiovascular disease event as the attending
physician has
little if any time to assess the renal function of that patient prior to
initiating treatment.
[0100] In the methods of this invention, the IV solution has a selected amount
of
ranolazine comprising from about 1.5 to 3 mg per milliliter of solution,
preferably
about 1.8 to 2.2 mg per milliliter and, even more preferably, about 2 mg per
milliliter.
In contrast to Kluge, et al., supra., the IV solution does not contain any
propylene
glycol or any polyethylene glycol. Rather the compositions of this invention
comprise
ranolazine, sterile water and dextrose monohydrate or sodium chloride. As
such, the
compositions of this invention are less viscous than those described by Kluge
et al.
allowing for more efficient rapid titration of the patient with the IV
solution.
[0101] The IV solution of this invention is different from the injectable
formulations
since injectable formulations typically have excipients that may not be needed
and may
be contraindicated for IV formulations of this invention. For example, an
injectable
formulation can have an anti-spasmodic agent such as gluconic acid. As such,
the IV
solutions of this invention do not contain such anti-spasmodic agents and
especially
gluconic acid.
21
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0102] The IV solution of this invention is used to stabilize a diabetic, pre-
diabetic, or
non-diabetic patient suffering from an acute cardiovascular disease event. In
particular,
the presenting patient is immediately administered this IV solution of
ranolazine for a
period until the patient is stabilized. Such stabilization typically occurs
within from
about 12 to about 96 hours.
[0103] In a preferred embodiment, the patient suffering from an acute
cardiovascular
disease event is treated by:
[0104] initiating administration of an IV solution to said patient wherein
said IV
solution comprises a selected concentration of ranolazine of from about 1.5 to
about 3
mg per milliliter, preferably about 1.8 to about 2.2 mg per milliliter and,
even more
preferably, about 2 mg per milliliter;
[0105] titrating the IV administration of the IV ranolazine solution to the
patient
comprising: i) a sufficient amount of the IV solution to provide for about 200
mg of
ranolazine delivered to the patient over about a 1 hour period; ii) followed
by either: a
sufficient amount of the IV solution to provide for about 80 mg of ranolazine
per hour;
or if said patient is suffering from renal insufficiency, a sufficient amount
of the IV
solution to provide for about 40 mg of ranolazine per hour; and
[0106] maintaining the titration of b) above until the patient stabilizes
which typically
occurs within from about 12 to about 96 hours.
[0107] In one embodiment, the infusion of the intravenous formulation of
ranolazine is
initiated such that a target peak ranolazine plasma concentration of about
2500 ng
base/mL (wherein ng base/mL refers to ng of the free base of ranolazine/mL) is
achieved.
[0108] The downward adjustment of ranolazine infusion for a patient
experiencing
adverse events deemed to be treatment related, is within the knowledge of the
skilled in
the art and, based on the concentration of ranolazine in the IV solution, easy
to achieve.
Adverse events in addition to those described above include, but are not
limited to,
profound and persistent QTc prolongation, not attributed to other reversible
factors
such as hypokalemia; dizziness; nausea/vomiting; diplopia; parasthesia;
confusion; and
orthostatic hypotension. In one embodiment, the dose of intravenous solution
of
ranolazine may be adjusted to a lower dose such as, but not limited to, about
60 mg/hr,
about 40 mg/hr, or about 30 mg/hr. In another embodiment, the intravenous
delivery of
22
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
ranolazine may be temporarily discontinued for 1-3 hrs and then restarted at
the same
or lower dose for patients experiencing adverse events deemed to be treatment
related.
[0109] In a preferred embodiment, once stabilized the diabetic, pre-diabetic,
or non-
diabetic patient is then administered an oral sustained release formulation of
ranolazine.
Specifically, this invention is particularly useful for treating a high risk
coronary
disease patient with a subsequent acute coronary disease event by treating a
patient
with ranolazine. A high risk coronary patient is one who previously had at
least one
acute coronary disease event. In a preferred embodiment, a high risk patient
has a
TIMI risk score of 3 or higher.
[0110] In one embodiment, the oral dose of ranolazine is administered about 1
hour
prior to the termination of the intravenous infusion of ranolazine. In one
aspect of this
embodiment, at the time of transition from intravenous to oral dose, for the
intravenous
dose of ranolazine of about 80 mg/hr, the oral dose administered is 1000 mg
once or
twice daily (2 x 500 mg). In another aspect of this embodiment, at the time of
transition from intravenous to oral dose, for the intravenous dose of
ranolazine of about
60 mg/hr, the oral dose administered is 750 mg once or twice daily (2 x 375
mg). In
still another aspect of this embodiment, at the time of transition from
intravenous to
oral dose, for the intravenous dose of ranolazine of about 40 mg/hr, the oral
dose
administered is 500 mg (1 x 500 mg). In still another aspect of this
embodiment, at the
time of transition from intravenous to oral dose, for the intravenous dose of
ranolazine
of about 30 mg/hr, the oral dose administered is 375 mg (1 x 375 mg).
[0111] The downward adjustment of the oral dose for a patient experiencing
adverse
events deemed to be treatment related, is also within the knowledge of the
skilled in the
art. For example, the oral dose of ranolazine can be adjusted for patients
with newly
developed severe renal insufficiency. Other adverse events include, but are
not limited
to, profound and persistent QTc prolongation, not attributed to other
reversible factors
such as hypokalemia; dizziness; nausea/vomiting; diplopia; parasthesia;
confusion; and
orthostatic hypotension. In one embodiment, the oral dose of ranolazine may be
adjusted downward to 500 mg once or twice daily, if not already at this dose
or lower.
In one embodiment, the oral dose of ranolazine may be adjusted to the next
lower dose
such as, but not limited to, 750 mg once or twice daily, 500 mg once or twice
daily, or
375 mg once or twice daily.
23
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0112] In one embodiment, a starting oral dose of 375 mg once or twice daily
may be
administered to a patient treated with moderate CYP3A inhibitors, such as,
diltiazem
>180 mg/day, fluconazole and the like, and P-gp inhibitors such as, verapamil,
cyclosporine and the like. In one embodiment, the 1000 mg oral dose of
ranolazine is
administered such that a mean peak ranolazine plasma concentration of about
2500 ng
base/mL + 1000 ng base/mL is achieved.
[0113] In one embodiment, the invention relates to a method for reducing
ischemia
associated with cardiovascular intervention in a patient comprising
intravenously
administering an intravenous formulation of ranolazine at least about 4 hours
and
preferably about 6 hours prior to intervention. In a further aspect of this
embodiment,
the invention further comprises continuing to administer the ranolazine
intravenously
for at least about 4 hours and preferably about 6 hours after the
intervention.
[0114] In a preferred embodiment, a patient receives intravenous ranolazine
for at least
about 4 hours or at least about 6 hours prior to the intervention and then
receives
intravenous ranolazine for at least about 4 hours or at least about 6 hours
after
intervention.
[0115] In these embodiments of the invention, the ranolazine intravenously
administered is an intravenous formulation as described herein.
[0116] Without limiting the scope of the invention, the formulations of the
invention
can be used for treating various diseases, such as, cardiovascular diseases
e.g.,
arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia,
arrhythmia due to
myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia
after
PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy,
myocardial
infarction, heart failure (e.g., congestive heart failure, acute heart
failure, cardiac
hypertrophy, etc.), restenosis after PTCA, PTCI (percutaneous transluminal
coronary
intervention), and shock (e.g., hemorrhagic shock, endotoxin shock, etc.);
renal
diseases e.g., diabetes mellitus, diabetic nephropathy, ischemic acute renal
insufficiency, etc.; organ disorders associated with ischemia or ischemic
reperfusion
e.g., heart muscle ischemic reperfusion associated disorders, acute renal
insufficiency,
or disorders induced by surgical treatment such as CABG (coronary artery
bypass
grafting) surgeries, vascular surgeries, organ transplantation, non-cardiac
surgeries or
PTCA; cerebrovascular diseases e.g., ischemic stroke, hemorrhagic stroke,
etc.; cerebro
24
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
ischemic disorders e.g., disorders associated with cerebral infarction,
disorders caused
after cerebral apoplexy such as sequelae, or cerebral edema; and ischemia
induced in
donor tissues used in transplants where donor tissues include but are not
limited to,
renal transplants, skin grafts, cardiac transplants, lung transplants, corneal
transplants,
and liver transplants. The formulations of this invention can also be used as
an agent for
myocardial protection during CABG surgeries, vascular surgeries, PTCA, PTCI,
organ
transplantation, or non-cardiac surgeries.
[0117] Preferably, the formulations of this invention can be used for
myocardial protection before,
during, or after CABG surgeries, vascular surgeries, PTCA, organ
transplantation, or non-cardiac
surgeries. Preferably, the formulations of this invention can be used for
myocardial protection in patients
presenting with ongoing cardiac (acute coronary syndromes, e.g., myocardial
infarction or unstable
angina) or cerebral ischemic events (e.g., stroke). Preferably, the
formulations of this invention can be
used for chronic myocardial protection in patients with diagnosed coronary
heart disease (e.g., previous
myocardial infarction or unstable angina) or patients who are at high risk for
myocardial infarction (age
greater than 65 and two or more risk factors for coronary heart disease).
Compositions of the invention
Intravenous Formulation
[0118] In one aspect, the invention provides an intravenous (IV) solution
comprising a
selected concentration of ranolazine. Specifically, the IV solution preferably
comprises
about 1.5 to about 3.0 mg of ranolazine per milliliter of a pharmaceutically
acceptable
aqueous solution, more preferably about 1.8 to about 2.2 mg and even more
preferably
about 2 mg. In order to allow for the rapid intravenous flow of ranolazine
into the
patient, the IV solution preferably contains no viscous components including
by way of
example as propylene glycol or polyethylene glycol (e.g., polyethylene
glyco1400). It
is understood that minor amounts of viscous components that do not materially
alter the
viscosity may be included in the intravenous formulations of this invention.
In a
particularly preferred embodiment, the viscosity of the IV solution is
preferably less
than 10 cSt (centistokes) at 20 C, more preferably less than 5 cSt at 20 C and
even
more preferably less than 2 cSt at 20 C.
[0119] In one embodiment, the IV solution comprises:
about 1.5 to about 3.0 mg of ranolazine per mL of IV solution; and
either about 4.8 to about 5.0 weight percent dextrose or about 0.8 to about
1.0
weight percent sodium chloride.
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
[0120] In one embodiment, the IV solution comprises:
about 1.8 to about 2.2 mg of ranolazine per mL of IV solution; and
either about 4.8 to about 5.0 weight percent dextrose or about 0.8 to about
1.0
weight percent sodium chloride.
[0121] In one embodiment, the IV solution of this invention comprises:
about 2 mg of ranolazine per mL of IV solution; and
either about 4.8 to about 5.0 weight percent dextrose or about 0.9 weight
percent sodium chloride.
[0122] The IV solutions described herein can be prepared from a stock solution
comprising a 20 mL container for single use delivery which container comprises
a
sterile aqueous solution of ranolazine at a concentration of about 25 mg/mL;
either
about 36 mg/mL dextrose monohydrate or about 0.9 weight percent sodium
chloride;
and having a pH of about 4. Surprisingly, employing such high concentrations
of
ranolazine and dextrose monohydrate or ranolazine and sodium chloride in the
stock
solutions provide for compositions which are stable and have adequate shelf-
lives,
preferably of greater than 6 months.
[0123] Exemplary methods for preparing the stock solutions are described in
Examples
l and 2.
[0124] In a typical setting, two 20 mL containers described herein are
injected into an
IV container containing 460 mL of sterile saline (0.9 weight percent (w%)
sodium
chloride) or an aqueous dextrose solution (water containing 5 weight percent
dextrose
monohydrate) to provide for an IV solution of about 2 mg/mL of ranolazine
maintained
at physiologically acceptable pH. Containers useful herein include, but are
not limited
to, vials, syringes, bottles, IV bags, and the like.
[0125] In another embodiment, the intravenous formulation as above, is diluted
with a
sterile diluent prior to use. In one embodiment, the sterile diluent is 5 %
dextrose or a
0.9 weight percent saline solution. In one embodiment, the intravenous
formulation is
further diluted into bags of sterile diluent.
Oral Formulation
[0126] In one embodiment, a formulation of ranolazine is an oral formulation.
In one
embodiment, an oral formulation of ranolazine is a tablet. In one embodiment,
the
tablet of ranolazine is up to 500 mg. In another embodiment, the tablet of
ranolazine is
26
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
up to 1000 mg. In a preferred embodiment, the ranolazine tablet is 375 mg,
and/or 500
mg.
[0127] The oral formulation of ranolazine is thoroughly discussed in U.S.
Patent No.
6,303,607 and U.S. Publication No. 2003/0220344, which are both incorporated
herein
by reference in their entirety.
[0128] The oral sustained release ranolazine dosage formulations of this
invention are
administered one, twice, or three times in a 24 hour period in order to
maintain a
plasma ranolazine level above the threshold therapeutic level and below the
maximally
tolerated levels, which is preferably a plasma level of about 550 to 7500 ng
base/mL in
a patient.
[0129] In a preferred embodiment, the plasma level of ranolazine ranges about
1500-
3500 ng base/mL.
[0130] In order to achieve the preferred plasma ranolazine level, it is
preferred that the
oral ranolazine dosage forms described herein are administered once or twice
daily. If
the dosage forms are administered twice daily, then it is preferred that the
oral
ranolazine dosage forms are administered at about twelve hour intervals.
[0131] In addition to formulating and administering oral sustained release
dosage forms
of this invention in a manner that controls the plasma ranolazine levels, it
is also
important to minimize the difference between peak and trough plasma ranolazine
levels. The peak plasma ranolazine levels are typically achieved at from about
30
minutes to eight hours or more after initially ingesting the dosage form while
trough
plasma ranolazine levels are achieved at about the time of ingestion of the
next
scheduled dosage form. It is preferred that the sustained release dosage forms
of this
invention are administered in a manner that allows for a peak ranolazine level
no more
than 8 times greater than the trough ranolazine level, preferably no more than
4 times
greater than the trough ranolazine level, preferably no more than 3 times
greater than
the trough ranolazine level, and most preferably no greater than 2 times
trough
ranolazine level.
[0132] The sustained release ranolazine formulations of this invention provide
the
therapeutic advantage of minimizing variations in ranolazine plasma
concentration
while permitting, at most, twice-daily administration. The formulation may be
administered alone, or (at least initially) in combination with an immediate
release
27
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
formulation if rapid achievement of a therapeutically effective plasma
concentration of
ranolazine is desired or by soluble IV formulations and oral dosage forms.
[0133] Without limiting the scope of the invention, the formulations of the
invention
can be used for treating various diseases, such as, cardiovascular diseases
e.g.,
arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia,
arrhythmia due to
myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia
after
PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy,
myocardial
infarction, heart failure (e.g., congestive heart failure, acute heart
failure, cardiac
hypertrophy, etc.), restenosis after PTCA, PTCI (percutaneous transluminal
coronary
intervention), and shock (e.g., hemorrhagic shock, endotoxin shock, etc.);
renal
diseases e.g., diabetes mellitus, impaired glucose tolerance or pre-diabetes,
diabetic
nephropathy, ischemic acute renal insufficiency, etc.; organ disorders
associated with
ischemia or ischemic reperfusion e.g., heart muscle ischemic reperfusion
associated
disorders, acute renal insufficiency, or disorders induced by surgical
treatment such as
CABG (coronary artery bypass grafting) surgeries, vascular surgeries, organ
transplantation, non-cardiac surgeries or PTCA; cerebrovascular diseases e.g.,
ischemic
stroke, hemorrhagic stroke, etc.; cerebro ischemic disorders e.g., disorders
associated
with cerebral infarction, disorders caused after cerebral apoplexy such as
sequelae, or
cerebral edema; and ischemia induced in donor tissues used in transplants
where donor
tissues include but are not limited to, renal transplants, skin grafts,
cardiac transplants,
lung transplants, corneal transplants, and liver transplants. The formulations
of this
invention can also be used as an agent for myocardial protection during CABG
surgeries, vascular surgeries, PTCA, PTCI, organ transplantation, or non-
cardiac
surgeries.
[0134] Preferably, the formulations of this invention can be used for
myocardial
protection before, during, or after CABG surgeries, vascular surgeries, PTCA,
organ
transplantation, or non-cardiac surgeries. Preferably, the formulations of
this invention
can be used for myocardial protection in patients presenting with ongoing
cardiac
(acute coronary syndromes, e.g., myocardial infarction or unstable angina) or
cerebral
ischemic events (e.g., stroke). Preferably, the formulations of this invention
can be
used for chronic myocardial protection in patients with diagnosed coronary
heart
disease (e.g., previous myocardial infarction or unstable angina) or patients
who are at
28
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
high risk for myocardial infarction (age greater than 65 and two or more risk
factors for
coronary heart disease).
Pharmaceutical Compositions and Administration
[0135] The compounds of the invention are usually administered in the form of
pharmaceutical compositions. This invention therefore provides pharmaceutical
compositions that contain, as the active ingredient, one or more of the
compounds of
the invention, or an isomer thereof, or a pharmaceutically acceptable salt or
ester
thereof, and one or more pharmaceutically acceptable excipients, carriers,
including
inert solid diluents and fillers, diluents, including sterile aqueous solution
and various
organic solvents, permeation enhancers, solubilizers and adjuvants. The
compounds of
the invention may be administered alone or in combination with other
therapeutic
agents. Such compositions are prepared in a manner well known in the
pharmaceutical
art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co.,
Philadelphia, PA 17 th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker,
Inc. 3rd
Ed. (G.S. Banker & C.T. Rhodes, Eds.).
[0136] One preferred mode for administration is parental, particularly by
injection.
The forms in which the novel compositions of the present invention may be
incorporated for administration by injection include aqueous or oil
suspensions, or
emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well
as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical
vehicles.
Aqueous solutions in saline are also conventionally used for injection, but
less
preferred in the context of the present invention. Ethanol, glycerol,
propylene glycol,
liquid polyethylene glycol, and the like (and suitable mixtures thereof),
cyclodextrin
derivatives, and vegetable oils may also be employed. The proper fluidity can
be
maintained, for example, by the use of a coating, such as lecithin, by the
maintenance
of the required particle size in the case of dispersion and by the use of
surfactants. The
prevention of the action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example, parabens, chlorobutanol,
phenol,
sorbic acid, thimerosal, and the like.
[0137] Sterile injectable solutions are prepared by incorporating the compound
of the
invention in the required amount in the appropriate solvent with various other
ingredients as enumerated above, as required, followed by filtration and
sterilization.
Generally, dispersions are prepared by incorporating the various sterilized
active
29
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
ingredients into a sterile vehicle which contains the basic dispersion medium
and the
required other ingredients from those enumerated above. In the case of sterile
powders
for the preparation of sterile injectable solutions, the preferred methods of
preparation
are vacuum-drying and freeze-drying techniques which yield a powder of the
active
ingredient plus any additional desired ingredient from a previously sterile-
filtered
solution thereof
[0138] Oral administration is another route for administration of the
compounds of
Formula I. Administration may be via tablet, capsule or enteric-coated
tablets, or the
like. In making the pharmaceutical compositions that include at least one
compound of
either Formula I, the active ingredient is usually diluted by an excipient
and/or enclosed
within a carrier such that the formulation can be in the form of a capsule,
sachet, paper
or other container. When the excipient serves as a diluent, it can be a solid,
semi-solid,
or liquid material (as above), which acts as a vehicle, carrier or medium for
the active
ingredient. Thus, the compositions can be in the form of tablets, pills,
powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,
syrups, aerosols
(as a solid or in a liquid medium), ointments containing, for example, up to
10% by
weight of the active compound, soft and hard gelatin capsules, sterile
injectable
solutions, and sterile packaged powders.
[0139] Some examples of suitable excipients include lactose, dextrose,
sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth,
gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose,
sterile water, syrup, and methyl cellulose. The formulations can additionally
include:
lubricating agents such as talc, magnesium stearate, and mineral oil; wetting
agents;
emulsifying and suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[0140] The compositions of the invention can be formulated so as to provide
quick,
sustained or delayed release of the active ingredient after administration to
the patient
by employing procedures known in the art. Controlled release drug delivery
systems
for oral administration include osmotic pump systems and dissolutional systems
containing polymer-coated reservoirs or drug-polymer matrix formulations.
Examples
of controlled release systems are given in U.S. Patent Nos. 3,845,770;
4,326,525;
4,902,514; 5,616,345; and WO 0013687. Another formulation for use in the
methods
of the present invention employs transdermal delivery devices ("patches").
Such
transdermal patches may be used to provide continuous or discontinuous
infusion of the
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
compounds of the present invention in controlled amounts. The construction and
use of
transdermal patches for the delivery of pharmaceutical agents is well known in
the art.
See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches
may be
constructed for continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0141] The compositions are preferably formulated in a unit dosage form. The
term
"unit dosage forms" refers to physically discrete units suitable as unitary
dosages for
human subjects and other mammals, each unit containing a predetermined
quantity of
active material calculated to produce the desired therapeutic effect, in
association with
a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The
compounds
of Formula I are effective over a wide dosage range and are generally
administered in a
pharmaceutically effective amount. Preferably, for oral administration, each
dosage
unit contains from 10 mg to 2 g of a compound of Formula I, more preferably 10
to
1500 mg, more preferably from 10 to 1000 mg, more preferably from 10 to 700
mg,
and for parenteral administration, preferably from 10 to 700 mg of a compound
of
Formula I, more preferably about 50 to 200 mg. It will be understood, however,
that
the amount of the compound of Formula I actually administered will be
determined by
a physician, in the light of the relevant circumstances, including the
condition to be
treated, the chosen route of administration, the actual compound administered
and its
relative activity, the age, weight, and response of the individual patient,
the severity of
the patient's symptoms, and the like.
[0142] For preparing solid compositions such as tablets, the principal active
ingredient
is mixed with a pharmaceutical excipient to form a solid preformulation
composition
containing a homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it is meant
that the
active ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage forms
such as
tablets, pills and capsules.
[0143] The tablets or pills of the present invention may be coated or
otherwise
compounded to provide a dosage form affording the advantage of prolonged
action, or
to protect from the acid conditions of the stomach. For example, the tablet or
pill can
comprise an inner dosage and an outer dosage component, the latter being in
the form
of an envelope over the former. The two components can be separated by an
enteric
layer that serves to resist disintegration in the stomach and permits the
inner component
to pass intact into the duodenum or to be delayed in release. A variety of
materials can
31
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
be used for such enteric layers or coatings, such materials including a number
of
polymeric acids and mixtures of polymeric acids with such materials as
shellac, cetyl
alcohol, and cellulose acetate.
[0144] In one embodiment, the preferred compositions of the invention are
formulated
so as to provide quick, sustained or delayed release of the active ingredient
after
administration to the patient, especially sustained release formulations. The
most
preferred compound of the invention is ranolazine, which is named
( )-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2 methoxyphenoxy)
propyl]-1-piperazine-acetamide, or its isomers, or its pharmaceutically
effective salts.
Unless otherwise stated, the ranolazine plasma concentrations used in the
specification
and examples refer to ranolazine free base.
[0145] The preferred sustained release formulations of this invention are
preferably in
the form of a compressed tablet comprising an intimate mixture of compound and
a
partially neutralized pH-dependent binder that controls the rate of
dissolution in
aqueous media across the range of pH in the stomach (typically approximately
2) and in
the intestine (typically approximately about 5.5). An example of a sustained
release
formulation is disclosed in U.S. Patents 6,303,607; 6,479,496; 6,369,062; and
6,525,057, the complete disclosures of which are hereby incorporated by
reference.
[0146] To provide for a sustained release of compound, one or more pH-
dependent
binders are chosen to control the dissolution profile of the compound so that
the
formulation releases the drug slowly and continuously as the formulation
passed
through the stomach and gastrointestinal tract. The dissolution control
capacity of the
pH-dependent binder(s) is particularly important in a sustained release
formulation
because a sustained release formulation that contains sufficient compound for
twice
daily administration may cause untoward side effects if the compound is
released too
rapidly ("dose-dumping").
[0147] Accordingly, the pH-dependent binders suitable for use in this
invention are
those which inhibit rapid release of drug from a tablet during its residence
in the
stomach (where the pH is below about 4.5), and which promotes the release of a
therapeutic amount of compound from the dosage form in the lower
gastrointestinal
tract (where the pH is generally greater than about 4.5). Many materials known
in the
pharmaceutical art as "enteric" binders and coating agents have the desired pH
dissolution properties. These include phthalic acid derivatives such as the
phthalic acid
derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses,
alkylcelluloses,
32
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers,
alkylcellulose
acetates, and the partial esters thereof, and polymers and copolymers of lower
alkyl
acrylic acids and lower alkyl acrylates, and the partial esters thereof
[0148] Preferred pH-dependent binder materials that can be used in conjunction
with
the compound to create a sustained release formulation are methacrylic acid
copolymers. Methacrylic acid copolymers are copolymers of methacrylic acid
with
neutral acrylate or methacrylate esters such as ethyl acrylate or methyl
methacrylate. A
most preferred copolymer is methacrylic acid copolymer, Type C, USP (which is
a
copolymer of methacrylic acid and ethyl acrylate having between 46.0% and
50.6%
methacrylic acid units). Such a copolymer is commercially available, from R6hm
Pharma as Eudragit L 100-55 (as a powder) or L30D-55 (as a 30% dispersion in
water). Other pH-dependent binder materials which may be used alone or in
combination in a sustained release formulation dosage form include
hydroxypropyl
cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose
acetate
phthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, and the
like.
[0149] One or more pH-independent binders may be in used in sustained release
formulations in oral dosage forms. It is to be noted that pH-dependent binders
and
viscosity enhancing agents such as hydroxypropyl methylcellulose,
hydroxypropyl
cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate
esters, and
the like, may not themselves provide the required dissolution control provided
by the
identified pH-dependent binders. The pH-independent binders may be present in
the
formulation of this invention in an amount ranging from about 1 to about 10
wt%, and
preferably in amount ranging from about 1 to about 3 wt% and most preferably
about
2.0 wt%.
[0150] As shown in Table 1, the preferred compound of the invention,
ranolazine, is
relatively insoluble in aqueous solutions having a pH above about 6.5, while
the
solubility begins to increase dramatically below about pH 6.
Table 1
Solution pH Solubility (mg/mL) USP Solubility Class
4.81 161 Freely Soluble
4.89 73.8 Soluble
4.90 76.4 Soluble
33
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
5.04 49.4 Soluble
5.35 16.7 Sparingly Soluble
5.82 5.48 Slightly soluble
6.46 1.63 Slightly soluble
6.73 0.83 Very slightly soluble
7.08 0.39 Very slightly soluble
7.59 (unbuffered water) 0.24 Very slightly soluble
7.79 0.17 Very slightly soluble
12.66 0.18 Very slightly soluble
[0153] Increasing the pH-dependent binder content in the formulation decreases
the
release rate of the sustained release form of the compound from the
formulation at pH
is below 4.5 typical of the pH found in the stomach. The enteric coating
formed by the
binder is less soluble and increases the relative release rate above pH 4.5,
where the
solubility of compound is lower. A proper selection of the pH-dependent binder
allows
for a quicker release rate of the compound from the formulation above pH 4.5,
while
greatly affecting the release rate at low pH. Partial neutralization of the
binder
facilitates the conversion of the binder into a latex like film which forms
around the
individual granules. Accordingly, the type and the quantity of the pH-
dependent binder
and amount of the partial neutralization composition are chosen to closely
control the
rate of dissolution of compound from the formulation.
[0154] The dosage forms of this invention should have a quantity of pH-
dependent
binders sufficient to produce a sustained release formulation from which the
release
rate of the compound is controlled such that at low pHs (below about 4.5) the
rate of
dissolution is significantly slowed. In the case of methacrylic acid
copolymer, type C,
USP (Eudragit L 100-55), a suitable quantity of pH-dependent binder is
between 5%
and 15%. The pH dependent binder will typically have from about 1 to about 20
% of
the binder methacrylic acid carboxyl groups neutralized. However, it is
preferred that
the degree of neutralization ranges from about 3 to 6%. The sustained release
formulation may also contain pharmaceutical excipients intimately admixed with
the
compound and the pH-dependent binder. Pharmaceutically acceptable excipients
may
include, for example, pH-independent binders or film-forming agents such as
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,
34
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. the methyl
methacrylate/ethyl acrylate copolymers sold under the trademark Eudragit NE
by
R6hm Pharma, starch,gelatin, sugars carboxymethylcellulose, and the like.
Other
useful pharmaceutical excpients include diluents such as lactose, mannitol,
dry starch,
microcrystalline cellulose and the like; surface active agents such as
polyoxyethylene
sorbitan esters, sorbitan esters and the like; and coloring agents and
flavoring agents.
Lubricants (such as tale and magnesium stearate) and other tableting aids are
also
optionally present.
[0155] The sustained release formulations of this invention have an active
compound
content of above about 50% by weight to about 95% or more by weight, more
preferably between about 70% to about 90% by weight and most preferably from
about
70 to about 80% by weight; a pH-dependent binder content of between 5% and
40%,
preferably between 5% and 25%, and more preferably between 5% and 15%; with
the
remainder of the dosage form comprising pH-independent binders, fillers, and
other
optional excipients.
One particularly preferred sustained release formulations of this invention is
shown
below in Table 2.
Table 2.
Ingredient Weight Preferred Most Preferred
Range (%) Range (%)
Active ingredient 50-95 70-90 75
Microcrystalline cellulose (filler) 1-35 5-15 10.6
Methacrylic acid copolymer 1-35 5-12.5 10.0
Sodium hydroxide 0.1-1.0 0.2-0.6 0.4
Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0
Magnesium stearate 0.5-5.0 1-3 2.0
[0156] The sustained release formulations of this invention are prepared as
follows: compound and pH-dependent binder and any optional excipients are
intimately
mixed(dry-blended). The dry-blended mixture is then granulated in the presence
of an
aqueous solution of a strong base that is sprayed into the blended powder. The
granulate is dried, screened, mixed with optional lubricants (such as talc or
magnesium
stearate), and compressed into tablets. Preferred aqueous solutions of strong
bases are
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
solutions of alkali metal hydroxides, such as sodium or potassium hydroxide,
preferably sodium hydroxide, in water (optionally containing up to 25% of
water-miscible solvents such as lower alcohols).
[0157] The resulting tablets may be coated with an optional film-forming
agent, for
identification, taste-masking purposes and to improve ease of swallowing. The
film
forming agent will typically be present in an amount ranging from between 2%
and 4%
of the tablet weight. Suitable film-forming agents are well known to the art
and include
hydroxypropyl. methylcellulose, cationic methacrylate copolymers
(dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers -
Eudragit
E - R6hm. Pharma), and the like. These film-forming agents may optionally
contain
colorants, plasticizers, and other supplemental ingredients.
[0158] The compressed tablets preferably have a hardness sufficient to
withstand 8 Kp
compression. The tablet size will depend primarily upon the amount of compound
in
the tablet. The tablets will include from 300 to 1100 mg of compound free
base.
Preferably, the tablets will include amounts of compound free base ranging
from
400-600 mg, 650-850 mg, and 900-1100 mg.
[0159] In order to influence the dissolution rate, the time during which the
compound
containing powder is wet mixed is controlled. Preferably the total powder mix
time,
i.e. the time during which the powder is exposed to sodium hydroxide solution,
will
range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following
granulation,
the particles are removed from the granulator and placed in a fluid bed dryer
for drying
at about 60 C.
[0160] It has been found that these methods produce sustained release
formulations that
provide lower peak plasma levels and yet effective plasma concentrations of
compound
for up to 12 hours and more after administration, when the compound is used as
its free
base, rather than as the more pharmaceutically common dihydrochloride salt or
as
another salt or ester. The use of free base affords at least one advantage:
The
proportion of compound in the tablet can be increased, since the molecular
weight of
the free base is only 85% that of the dihydrochloride. In this manner,
delivery of an
effective amount of compound is achieved while limiting the physical size of
the
dosage unit.
36
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
Utility and Testin~
[0161] The method is effective in the treatment of diabetes.
[0162] Activity testing is conducted as described in the Examples below, and
by
methods apparent to one skilled in the art.
[0163] The Examples that follow serve to illustrate this invention. The
Examples are
intended to in no way limit the scope of this invention, but are provided to
show how to
make and use the compounds of this invention. In the Examples, all
temperatures are
in degrees Centigrade.
[0164] Examples 1-4 illustrate the preparation of representative
pharmaceutical
formulations containing a compound of Formula I.
EXAMPLE 1
[0165] 20-mL Type 1 flint vial of Ranolazine Injection filled to deliver 20 mL
(at 1, 5,
or 25 mg/mL ranolazine concentration).
Compositions:
Ranolazine 1.0, 5.0, 25.0 mg/mL
Dextrose monohydrate 55.0, 52.0, 36.0 mg/mL
Hydrochloric acid q.s. pH to 4.0 0.2
Sodium hydroxide q.s. pH to 4.0 0.2
Water for Injection q.s.
Container/Closure System:
Vial: Type 1 Flint, 20-cc, 20-mm finish
Stopper: Rubber, 20-mm, West 4432/50, gray butyl, teflon coated
Seal: Aluminum, 20-mm, flip-top oversea
Method of Manufacture
[0166] The intraveous formulation of ranolazine is manufactured via an aseptic
fill
process as follows. In a suitable vessel, the required amount of dextrose
monohydrate
was dissolved in Water for Injection (WFI) at about 78% of the final batch
weight.
With continuous stirring, the required amount of ranolazine was added to the
dextrose
solution. To facilitate the dissolution of ranolazine, the solution pH was
adjusted to a
target of 3.88-3.92 with an 0.1 N or 1.0 N HC1 solution. Additionally, 1 N
NaOH may
have been utilized to further adjust the solution to the target pH of 3.88-
3.92. After
37
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
ranolazine was dissolved, the batch was adjusted to the final weight with WFI.
Upon
confirmation that in-process specifications had been met, the ranolazine-
formulated
bulk solution was sterilized by sterile filtration through two 0.2 m sterile
filters.
Subsequently, the sterile ranolazine-formulated bulk solution was aseptically
filled into
sterile glass vials and aseptically stoppered with sterile stoppers. The
stoppered vials
were then sealed with clean flip-top aluminum overseals. The vials then went
through
a final inspection.
EXAMPLE 2
[0167] 20-mL Type 1 flint vial of Ranolazine Injection are filled to deliver
20 mL (25
mg/mL concentration).
Composition:
Ranolazine 25.0 mg/mL
Dextrose monohydrate 36.0 mg/mL
Hydrochloric acid Adjust pH to 3.3-4.7
Water for Injection q.s.
Container/Closure System:
Vial: Type 1 tubing, untreated, 20-mL, 20-mm finish
Stopper: Rubber, 20-mm, West 4432/50, gray butyl
Seal: Aluminum, 20-mm, blue flip-off overseal
Method of Manufacture
[0168] Water for Injection (WFI) is charged in a suitable vessel at about 90%
of the
final batch weight. About 90-95% of the required amount of 5 N HC1 is added
into the
compounding vessel. With continuous stirring, the required amount of
ranolazine is
slowly added, followed by the addition of dextrose monohydrate into the
ranolazine
solution. To solubilize ranolazine, the solution pH is adjusted with 5 N HC1
solution to
a target of 3.9-4.1. The batch is subsequently adjusted to the final weight
with WFI.
Upon confirmation that in-process specifications have been met, the ranolazine-
formulated bulk solution is sterilized by filtration through two redundant
0.22 m
sterilizing filters. The sterile ranolazine-formulated bulk solution is then
aseptically
filled into 20 mL sterile/depyrogenated vials and aseptically stoppered with
sterile/depyrogenated stoppers. The stoppered vials are sealed with clean flip-
top
38
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
aluminum overseals. The sealed vials are terminally sterilized by a validated
terminal
sterilization cycle at 121.1 C for 30 minutes. After the terminal
sterilization process,
the vials go through an inspection. To protect the drug product from light,
the vials are
individually packaged into carton boxes.
EXAMPLE 3
Patients with Diabetes or the Metabolic Syndrome Presenting with non-ST-
Elevation Acute Coronary Syndrome (NSTEACS)
Background
[0169] Data obtained from a clinical trial of patients admitted with non-ST
elevation
acute coronary syndrome (NSTEACS) was evaluated to determine the prevalence
and
outcome of those patients also suffering with diabetes and/or metabolic
syndrome. The
patients were treated with ranolazine which has been associated with improved
glycemic parameters. See United States Patent Application serial number,
10/443,314,
published as US 2004/0063717, incorporated by reference herein in its
entirety.
Methods
[0170] MERLIN-TIMI 36 randomized 6560 patients at presentation with NSTEACS
were treated with either placebo or the anti-ischemic agent ranolazine, which
has also
been associated with improved glycemic parameters. Median clinical follow-up
was 12
months. Metabolic syndrome was defined as having any 3 of the following: 1)
waist
circumference >102cm (men) and >88cm (women), 2) triglycerides (TG) >150 mg/dL
or drug treatment for elevated TG, 3) High density lipoproteins (HDL) <40
mg/dL
(men) and <50 mg/dL (women), or drug treatment for reduced HDL, 4) Systolic
blood
pressure (SBP) >130 mmHg or diastolic blood pressure (DBP) >85 mmHg or drug
treatment for hypertension, and 5) fasting glucose >100 mg/dL.
Results
[0171] At randomization, 2191(33.4%) of all patient carried a diagnosis of
diabetes
mellitus (DM) and 2628 (40.1%) patients had metabolic syndrome. Patients with
DM
and metabolic syndrome were more likely to be female and have known coronary
artery disease and had higher TIMI Risk scores at presentation, but were less
likely to
have an index diagnosis of NSTEMI (44.8% for DM v. 51.2% for metabolic
syndrome
v. 62.8% for no diagnosis, p<0.001). The rate of revascularization was similar
among
39
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
all groups (40.4% v. 39.7% v. 37.4%, p=0.11). There was a stepwise increase in
the
risk of severe recurrent ischemia, myocardial infarction, and cardiovascular
death in
patients with DM at highest risk followed by those with metabolic syndrome and
then
patients with neither at lowest risk. (Figure 1).
Conclusions
[0172] Metabolic syndrome and diabetes are common among patients presenting
with
NSTEACS and confer increased cardiovascular risk.
EXAMPLE 4
[0173] Sustained release tablets containing the following ingredients are
prepared:
Ingredient Weight A preferred
Ran e% Ranolazine Form'n (mg)
Ranolazine 75 500
Microcrystalline cellulose 10.6 70.7
(filler)
Methacrylic acid co ol mer 10.0 66.7
Sodium hydroxide 0.4 2.7
H drox ro 1 methylcellulose 2.0 13.3
Magnesium stearate 2.0 13.3
[0174] Compound and pH-dependent binder and any optional excipients are
intimately
mixed (dry-blended). The dry-blended mixture is then granulated in the
presence of an
aqueous solution of a strong base that is sprayed into the blended powder. The
granulate is dried, screened, mixed with optional lubricants (such as talc or
magnesium
stearate), and compressed into tablets. Preferred aqueous solutions of strong
bases are
solutions of alkali metal hydroxides, such as sodium or potassium hydroxide,
preferably sodium hydroxide, in water (optionally containing up to 25% of
water-miscible solvents such as lower alcohols).
[0175] The resulting tablets may be coated with an optional film-forming
agent, for
identification, taste-masking purposes and to improve ease of swallowing. The
film
forming agent will typically be present in an amount ranging from between 2%
and 4%
of the tablet weight. Suitable film-forming agents are well known to the art
and include
hydroxypropyl. methylcellulose, cationic methacrylate copolymers
(dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers -
Eudragit
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
E - R6hm. Pharma), and the like. These film-forming agents may optionally
contain
colorants, plasticizers, and other supplemental ingredients.
[0176] The compressed tablets preferably have a hardness sufficient to
withstand 8 Kp
compression. The tablet size will depend primarily upon the amount of compound
in
the tablet. The tablets will include from 300 to 1100 mg of compound free
base.
Preferably, the tablets will include amounts of compound free base ranging
from
400-600 mg, 650-850 mg, and 900-1100 mg.
[0177] In order to influence the dissolution rate, the time during which the
compound
containing powder is wet mixed is controlled. Preferably the total powder mix
time,
i.e. the time during which the powder is exposed to sodium hydroxide solution,
will
range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following
granulation,
the particles are removed from the granulator and placed in a fluid bed dryer
for drying
at about 60 C.
EXAMPLE 5
Hemoglobin Alc Assays:
[0178] HbAlc levels were assayed following a modification of the method of
Phillipov
(Components of total measurement error for hemoglobin Alc determination.
Phillipov,
G., et al. Clin. Chem. (2001), 47(10):1851). (see Figure 2)
EXAMPLE 6
Triglyceride Levels
[0179] Test compounds, dissolved in DMSO and suspended in 0.5% tylose, are
administered perorally by means of a pharyngeal tube to Syrian gold hamsters.
To
determine the CETP activity, blood samples (approximately 250µ1) are taken
by
retro-orbital puncture prior to the start of the experiment. The compounds are
subsequently administered perorally using a pharyngeal tube. Identical volumes
of
solvent without compounds are administered to the control animals.
Subsequently, the
animals are fasted. Then at various times, up to 24 hours after administration
of the
compounds, blood samples are taken by puncture of the retro-orbital venous
plexus.
[0180] The blood samples are coagulated by incubation at 4 C. overnight. The
samples
are centrifuged at 6000 X.g for 10 minutes. The concentration of cholesterol
and
triglycerides in the resulting serum are determined using modifications of
commercially
41
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
available enzyme tests (cholesterol enzymatic 14366 Merck, triglycerides 14364
Merck).
EXAMPLE 7.
[0181] In order to study the anti-diabetic actions of the compounds, insulin-
dependent
diabetes mellitus can be induced by chemical destruction of the pancreas with
an i.v.
injection of STZ (60 mg/kg, controls can be given saline vehicle). The volume
of the
injection is equivalent to 0.1 ml/100 g body weight. The injection is
delivered into the
pre-cannulated jugular vein of young (190-220 g) male Sprague Dawley rats (see
below
for procedure). At the same time osmotic mini pumps are implanted
subcutaneously
(see below for procedure) to deliver drugs at a constant rate over the course
of the
study. Depending on the length of the study, a second mini pump may need to be
implanted.
[0182] In order to confirm the diabetic state, animals have a blood sample
taken from
the tail (snip the end off the tail) and their blood glucose determined.
Animals with
blood glucose levels exceeding 13 mM are considered diabetic and randomized
into 4
groups. Two groups receive insulin injections subcutaneously daily to achieve
partial
glucose control (fasting glucose levels approximately 50% of uncontrolled
diabetic
animals). One of the partially controlled diabetic groups is treated with the
test
compound. In addition, two non-diabetic groups are included, one receives the
test
compound and one does not. Neither of the non-diabetic groups of rats receive
insulin.
[0183] On a weekly basis, 500 L blood samples are taken by retro-orbital eye
bleed,
in isofluorane-anesthetized animals for determinations of the following: blood
glucose,
serum non-esterified free fatty acids, serum triglycerides, HbAlc, serum
insulin, total
cholesterol, HDL cholesterol, and serum concentrations of the test compound.
Body
weight is also measured weekly.
[0184] Once stable HbAlc is reached, the study is terminated. When this is
established, animals are cannulated in the carotid artery following aseptic
techniques.
Blood pressure is measured in anesthetized and awake rats. The next day, an
oral
glucose tolerance test is performed. An oral glucose tolerance test involves
administering 1 g glucose/kg by gavage.
[0185] Arterial blood samples (0.3 ml) are collected through the jugular
catheter that
was previously used for measuring blood pressure, prior to and at 10, 20, 30,
and 60
42
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
min following the glucose challenge and the plasma separated for glucose and
insulin
assays.
Induction of STZ-diabetes and implantation of osmotic mini pumps.
[0186] Under isofluorane anesthesia, the tails of rats are cleaned with warm
water
followed by ethanol. A tail vein injection of either STZ or saline is made
under
anesthesia, using sterile needles and syringe and filter-sterilized solutions.
Following
i.v. injection, the area has pressure applied to prevent bleeding, and the
animal is placed
in a clean cage with sterile bedding. In addition to the STZ or saline
injection, at the
initial time of anesthesia, rats have mini-pumps implanted subcutaneously in
the neck
region. If the study proceeds beyond 4-weeks, a second implantation is
performed.
Basically, a small area of the neck is shaved and cleaned extensively with an
iodine
solution, a small 1-cm incision using a scalpel is made in the dermal layer
and the
pump is inserted aseptically port-first into the Sub-Q space. The incision is
then closed
with 1-2 surgical staples as required.
Implantation of carotid artery catheter for measurement of blood pressure and
implementation of oral glucose tolerance test.
[0187] Following conditions using sterile techniques and instruments, an
anesthetized
rat is laid on its back with the head toward the surgeon and lubricating
ointment placed
in both eyes. A midline incision is made along the neck to expose the left
common
carotid artery. A tunnel is made for the catheter using blunt dissection in
the
subcutaneous pocket on the dorsal section of the neck where it is
externalized. Half-
curved forceps are used to isolate the artery and soft plastic tubing passed
under the
posterior portion of the artery to temporarily impede the blood flow to the
isolated area.
The anterior portion of the external carotid artery is then ligated with a
piece of 4-0 silk
suture and light tension is created on the artery by anchoring a pair of
hemostats to the
ends of the suture material. The external carotid is then semi-transected and
a 0.033 or
0.040 mm O.D. catheter inserted and pushed toward the aorta, (around 2-3- cm
deep).
The catheter is tied in place, secured to the pectoral muscle to prevent
removal of the
catheter, and the anterior portion of the external carotid permanently ligated
and
observed for any leakage of blood. Externally, the catheter is tied at the
back of the
neck and a piece of suture tied around the knot leaving both ends about 2
inches long
for retrieval from under the skin. The knotted catheter is retracted back
under the skin
43
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
to prevent being pulled out by the rat. For blood pressure measurements, the
catheter is
attached to a pressure transducer and a data-acquisition system. For blood
glucose
tolerance testing, the catheter is attached to a needle and syringe for
collection of blood
samples.
EXAMPLE 8
[0188] In order to study the anti-diabetic actions of the compounds, insulin-
dependent
diabetes mellitus are induced by chemical destruction of the pancreas with an
i.v.
injection of STZ (60 mg/kg, controls are given saline vehicle). The volume of
the
injection is equivalent to 0.1 ml/100 g body weight. The injection is
delivered into the
pre-cannulated jugular vein of young (280-300 g) male Sprague Dawley rats with
2
catheters surgically implanted in the jugular vein and external carotid
artery. In order
to confirm the diabetic state, animals have a blood sample taken from the
cannula and
their blood glucose is determined. Animals with blood glucose levels exceeding
13
mM are considered diabetic. The pre-implanted catheter is flushed daily with
heparinized saline to maintain patency. One week after the induction of
diabetes, rats
undergo pharmacokinetic studies with the compounds of the invention. Animals
have
their catheters retrieved from under the skin and tested for patency. An
injection plug is
attached to a 19-gauge IV set, filled with 0.1% heparinized saline and the
needle end
inserted into the catheters. The test compound(s) is (are) administered via
the jugular
vein catheter either by bolus injection or steady infusion, or by oral gavage
(1 ml/kg
and 2m1/kg, respectively). At 10 time points using 5-6 animals, 300 l of
blood is
drawn from the line in the carotid artery and 300 l saline flushed in to
replace blood
volume. 300 l of blood at 10 time points from a 300 gm animal represents -
10% total
blood volume. If a 24-hour sample is drawn, the catheters are tied off at skin
level and
the animals returned to their cages. They are then sacrificed at 24 hours by
exanguination under anesthesia to collect the last blood sample. If there is
no 24- hour
sample, the animals are sacrificed by exanguination under anesthesia at the
last blood
collection.
EXAMPLE 9
Exercise Performance and Hemoglobin Alc in Angina Patients with Diabetes
[0189] The CARISA (Combination Assessment of Ranolazine in Stable Angina)
study
randomized 823 symptomatic chronic angina patients on diltiazem, atenolol or
44
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
amlodipine to ranolazine 750 mg bid, 1000 mg bid or placebo in a parallel,
double-
blind, 12 week study. Modified Bruce treadmill tests were performed at
baseline, and
after 2, 6, and 12 weeks of treatment at trough and peak plasma levels. The
ranolazine
formulation used in this study was that shown in Example 4.
[0190] Ranolazine prolonged exercise duration (ED) similarly in both diabetic
(D) and
non-diabetic (ND) patients at trough (Figure 3) and peak (Figure 4). The 750
mg dose
of ranolazine prolonged exercise duration at trough drug concentrations by 29
seconds
in angina patients with diabetes and by 22 seconds in non-diabetic angina
patients. The
1000 mg dose of ranolazine prolonged exercise duration at trough drug
concentrations
by 34 seconds in angina patients with diabetes and by 21 seconds in non-
diabetic
angina patients.
[0191] Time to angina increased on ranolazine (Figure 5) and angina frequency
decreased. The improvement with ranolazine was not significantly different in
D vs.
ND patients (treatment by diabetes interaction p-values _0.26). Adverse events
were
similar: 25%, 25% and 34% of D had at least one adverse event on placebo,
ranolazine
750 and 1000 mg respectively vs. 27%, 33%, and 32% in ND patients.
[0192] Ranolazine 750 and 1000 mg bid were associated with an average absolute
reduction HbAlc of 0.48 percentage points and 0.70 percentage points,
respectively
compared to placebo at 12 weeks (p <0.01) (Figure 6). The reductions were
greater in
those patients on insulin (0.8 and 1.1 percentage points, respectively)
(Figure 7).
Glucose and triglyceride values for the diabetic patients in the study are
shown in Table
2.Table 2
[0193] Glucose and Triglyceride Values (all diabetic patients)
Placebo RAN 750 m bid RAN 1000 m bid
Glucose m /dL
Baseline 177.8 10.8 168 8.0 165.2 7.8
Change from baseline 1.2 7.1 8.0 8.8 1.7 7.2
Tri 1 cerides m /dL
Baseline 233.0 56.8 192.0 14.5 196 17.5
Change from Baseline 26.3 21.2 21.2 13.5 -7.3 9.3
All values are Mean SEM
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
EXAMPLE 10
Carbohydrate and Lipid Parameters in MARISA and CARISA
[0194] Ranolazine (RAN) increased treadmill exercise capacity in patients with
chronic
angina both alone (MARISA, N=191) and when added to background anti-anginal
therapy with atenolol, diltiazem, or amlodipine (CARISA, N=823). Angina
frequency
and nitroglycerin consumption were reduced by ranolazine. The ranolazine
formulation used in the CARISA and MARISA studies was that shown in Example 4.
The most frequently reported adverse events (dizziness constipation and
nausea) were
generally mild and occurred in fewer than 10% of patients. The potential use
of
ranolazine in diabetics is of interest because approximately one in four
angina patients
has diabetes.
[0195] Efficacy and tolerability of ranolazine were similar in both diabetic
and non-
diabetic patients in both MARISA and CARISA. In diabetic patients in CARISA
(N=131), ranolazine 750 and 1000 mg bid were associated with a mean absolute
reduction in HbAlc of 0.48 percentage points and 0.70 percentage points,
respectively,
compared to placebo at 12 weeks (each p<0.01). The reductions versus placebo
were
greater in those patients on insulin (N=3 1; 0.84 and 1.05 percentage points),
on 750 and
1000 mg bid (p<0.02 and p<0.01), respectively. Fasting glucose was not
affected by
ranolazine in diabetic patients in CARISA, regardless of insulin treatment;
one
hypoglycemic episode was reported on placebo and one on ranolazine. After 12-
24
months of open-label treatment, HbA1c decreased from baseline in the diabetic
patients
by 1.1 percentage points. During the first 12 weeks of ranolazine treatment of
diabetic
patients in CARISA, mean total and LDL cholesterol increased by up to 16 and
11
mg/dL, respectively; however, because of mean increases in HDL cholesterol up
to 5
mg/dL, the HDL/LDL ratio changed little. Over 3 years of open-label treatment
in the
combined MARISA/CARISA diabetic population, total and LDL cholesterol
decreased
from baseline, while HDL cholesterol continued to increase.
46
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
EXAMPLE 11
Effect of Ranolazine on Hyperglycemia in the MERLIN-TIMI 36 Randomized
Controlled Trial
Background
[0196] A prospective evaluation of the effect of ranolazine on hyperglycemia
as part of
a randomized, double-blind, placebo-controlled trial in acute coronary
syndromes
(ACS).
Methods
[0197] MERLIN-TIMI 36 randomized patients with non-ST elevation ACS to
ranolazine or placebo to compare HbAlc (%) and the time to onset of worsening
hyperglycemia (>1% increase in HbAlc). HbAlc data are reported as least-square
means. Patients categorized as "diabetic" had been diagnosed as diabetic
before or at
the time of randomization. Patients categorized as "no diabetes" had not been
diagnosed as diabetic before or at the time of randomization. Some patients
characterized as "no diabetes" may have been diagnosed as "diabetic" during
the trial;
however, these patients are still listed in the "no diabetes" category in
Figure 8B.
Results
[0198] Among 4306 patients with serial measurements, ranolazine significantly
reduced HbAlc at 4 months compared with placebo (5.9% vs. 6.2%, change from
baseline -0.30 vs. -0.04 p=0.001). In patients with DM treated with
ranolazine, HbAlc
declined from 7.2 to 6.8 (A -0.64, p<0.001, see Figure 8A). As such, patients
with DM
were significantly more likely to achieve an HbAlc <7% at 4 months when
treated with
ranolazine versus placebo (59% vs. 49%, p<0.001). In addition, worsening of
hyperglycemia by 1 year of follow-up was less likely in diabetic patients
treated with
ranolazine (14.2% vs. 20.6%; HR 0.63; 95% CI 0.51, 0.77, p<0.001). Notably, in
patients without DM at randomization or baseline (fasting glucose <100 mg/dL
and
HbAlc <6%), the incidence of new fasting glucose >110 mg/dL or HbAlc _6% was
also reduced by ranolazine (31.8% vs. 41.2%; HR 0.68; 95% CI 0.53, 0.88;
p=0.003;
see Figure 8B). Reported hypoglycemia in patients with DM was similar between
treatment groups (3% vs 3%).
47
CA 02687381 2009-11-16
WO 2008/147417 PCT/US2007/070140
Conclusion
[0199] Ranolazine significantly improved HbAlc in patients with DM and reduced
the
incidence of newly increased HbAlc in those without evidence of previous
hyperglycemia.
48
