Note: Descriptions are shown in the official language in which they were submitted.
CA 02574987 2007-02-02
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NICOTINIC ACID COMPOSITIONS FOR TREATING
HYPERLIPIDEMIA AND RELATED METHODS THEREFOR
This application is a division of Canadian Patent Application Serial No.
2,283,159 filed March 6, 1998.
Field of the Invention
This invention generally relates to compositions of nicotinic acid useful for
treating hyperlipidemia and methods of treating hyperlipidemia employing such
compositions. More particularly, the present invention employs a composition
of
nicotinic acid, derivatives and mixtures thereof, and a swelling agent to form
a time
release sustaining composition for nocturnal or evening dosing. Specifically,
the
present invention employs a composition of nicotinic acid and hydroxypropyl
methylcellulose to treat hyperlipidemia in a once per day oral dosage form
given
during the evening hours.
Back rg ound
Nicotinic acid has been used for many years in the treatment of
hyperlipidemia. This compound has long been known to exhibit the beneficial
effects of reducing total cholesterol, low density lipoproteins or "LDL
cholesterol",
triglycerides and apolipoprotein a (Lp)a)) in the human body, while increasing
desirable high density lipoproteins or "HDL cholesterol".
Nicotinic acid has normally been administered three times per day
after meals. This dosing regimen is known to provide a very beneficial effect
on blood lipids as discussed in Knopp et al, "Contrasting Effects of
Unmodified and Time-Release Forms of Niacin on Lipoproteins in
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Hyperlipidemic Subjects: Clues to Mechanism of Action of Niacin"; Metabolism
34/7, 1985, page
647. The chief advantage of this profile is the ability of nicotinic acid to
decrease total
cholesterol, LDL cholesterol, triglycerides and Lp(a) while increasing HDL
particles. While such
a regimen does produce beneficial effects, cutaneous flushing and the like
still of3en occurs in the
5 hyperlipidemics to whom the compound is administered.
In order to avoid or reduce the cutaneous flushing, a number of materials have
been
suggested for administration with an effective antihyperlipidemic amount of
nicotinic acid,
including guar gum in U.S. Pat. No. 4,965,252, and mineral salts, as disclosed
in U.S. Pat. No.
5,023,245; or inorganic mapesium salts as reported in U.S. Pat. No. 4,911,917.
These materials
] 0 have been reported to avoid or reduce the cutaneous flushing side effect
commonly associated
with nicotinic acid treatment.
Another method of avoiding or reducing the side effects associated with
immediate release
niacin is the use of sustained release formulations. Sustained release
formulations are designed
to slowly release the compound from the tablet or capsule. The slow drug
release reduces and
prolongs blood levels of drug and thus minimizes the side effects. Sustained
release formulations
of niacin have been developed, such as NicobidTM capsules (Rhone-Poulenc
Rorer), Endur-acinT"'
(Innovite Corporation) and Pat. No. 5,126,145 which describes a sustained
release niacin
formulation containing two different types of hydroxypropyl methylcellulose
and a hydrophobic
component.
Studies in hyperlipidemic patients have been conducted with a number of
sustained release
niacin products. These studies have demonstrated that the sustained release
products do not have
the same advantageous lipid altering effects as immediate release niacin, and
in fact often have a
worse side effect profile compared to the immediate release product. The major
disadvantage of
the sustained release formulations, as can be seen in Knopp et al., 1985, is
the significantly lower
CA 02574987 2007-02-02
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reduction in triglycerides (-2% for the sustained release versus -38% for the
immediate release)
and lower increase in HDL cholesterol, represented at HDL: particles which are
known by the art
to be most beneficial, (=5% for the sustained release versus +37% for the
immediate release).
Additionally, sustained release niacin formulations have been noted as causing
greater
incidences of liver toxicity as described in Henken et al (Am J Med 91:1991
1991) and Dalton et
al (Am J Med 93 102 1992). There is also great concern regarding the potential
of these
formulations in disrupting glucose metabolism and uric acid levels.
In a recent edition of the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
(JAMA), an articles appeared which presented research results investigating
the liver toxicity
problems associated with a sustained release form of nicotinic acid. "A
Comparison of the
Efficacy and Toxic Effects of Sustained- vs. Immediate-Release Niacin in
Hyperchoisterolemic
Patients", McKenney et al., JAMA, Vol. 271, No. 9, March 2, 1994, page 672,
The article
presented a study of twenty-three patients. Of that number, 12 or 52 percent
were forced to
withdraw because liver function tests (LFTs) increased indicating potential
liver damage. The
conclusion of the authors of that article was that the sustained release form
of niacin "should be
restricted from use."
A similar conclusion was reached in an article authored by representatives of
the Food and
Drug Administration and entitled "Hepatic Toxicity of Unmodified and Time-
Release Preparations
of Niacin", Rader, et al., THE AMERICAN JOURNAL OF MEDICINE, Vol. 92, January
1992,
page 77. Because of these studies and similar conclusions drawn by other
health care
professionals, the sustained release forms of niacin have experienced limited
utilization,
Therefore, it can be seen from the scientific literature that there is a need
for development
of a sustained release niacin formulation and a method of delivering said
formulation which would
provide hyperlipidemic patients with "balanced lipid alteration", i.e.
reductions in total cholesterol,
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LDL cholesterol, triglycerides and Lp(a) as well as increases in HDL
particles,
with an acceptable safety profile, especially as regards liver toxicity and
effects
on glucose metabolism and uric acid levels.
SUMMARY OF THE INVENTION
In brief, the present invention alleviates and overcomes certain of the above-
identified problems and shortcomings of the present state of nicotinic acid
therapy through the discovery of novel nicotinic acid formulations and methods
of treatment.
The present invention seeks to provide a composition of nicotinic acid or any
compound which is metabolized by the body to form nicotinic acid for treating
hyperlipidemia.
The present invention also seeks to provide a composition as above, which has
a time release sustaining characteristic.
The present invention also seeks to provide a method for employing a
composition as above, for treating hyperlipidemia, which results in little or
no
liver damage.
At least one or more of the foregoing, together with the advantages thereof
over
the known art relating to the treatment of hyperlipidemia, which shall become
apparent from the specification which follows, are accomplished by the
invention as hereinafter described.
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In accordance with one aspect of the invention there is provided an oral
dosage
pharmaceutical composition for daily treatment of hyperlipidemia in a patient
without inducing treatment-limiting liver damage, said composition comprising
an effective antihyperlipidemic amount of nicotinic acid for use as an oral
dose
once per day during the evening or at night, or before bedtime, as a single
dose,
wherein the nicotinic acid is combined with at least one pharmaceutically
acceptable carrier comprising a swelling agent in a total amount which
functions as a controlled release agent, to form an oral sustained release
solid
dosage form, and wherein the oral sustained release solid dosage form does not
contain an internal hydrophobic component, said, single daily oral dose
causing
little or no serious damage to the liver of the patient, said nicotinic acid
being
present in said dosage form in milled agglomerates of the nicotinic acid, a
portion of the total swelling agent, and a granulation binder, the
agglomerates
having been milled to a uniform particle size distribution, and said milled
agglomerates being blended, in said dosage form, with the remaining portion of
the total amount of swelling agent and an external lubricant.
In accordance with another aspect of the invention there is provided use of a
composition of the invention for treating hyperlipidemia in a patient without
inducing treatment-limiting (i) hepatotoxicity and (ii) abnormalities in uric
acid 20 levels or glucose levels or both.
In accordance with still another aspect of the invention there is provided a
method of manufacturing a base granulation for producing a sustained release
nicotinic acid solid dosage form, said method comprising:
(a) forming a wet granulation which consists essentially of nicotinic
acid, a portion of a total amount of a swelling agent which functions as a
controlled release agent, and a granulation binder;
(b) drying the wet granulation to form dry granules;
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(c) milling the dry granules to obtain a substantially uniform particle
size distribution;
(d) dry blending the milled dry granules, the remaining portion of the
total amount of swelling agent, and an external lubricant to form a final
dosage
blend; and
(e) forming the sustained release nicotinic acid solid dosage form
from the final dosage blend.
In accordance with another aspect of the invention, there is provided an oral
dosage sustained release pharmaceutical formulation for use once per day
during the evening or at night, or before bedtime, as a single dose, for daily
treatment of hyperlipidemia in a patient without inducing treatment-limiting
liver damage, said formulation comprising a compressed blend of nicotinic acid
in a hydrophilic matrix which controls delivery of said nicotinic acid, said
compressed blend comprising agglomerates and containing:
an effective antihyperlipidemic amount of nicotinic acid,
a swelling agent,
a granulation binder, and
a lubricant;
wherein said swelling agent is a hydrophillic polymer which on initial
wetting starts to partially hydrate forming a gel layer, such that as water
permeates into the formulation the thickness of the gel layer increases and
the
nicotinic acid diffuses out of the gel layer and an outer layer of the
formulation
erodes with increasing hydration, whereby said swelling agent of the
hydophilic matrix provides controlled sustained release of said nicotinic acid
from said hydophilic matrix, whereby said blend forms an oral sustained
release solid dosage form in which said sustained release is without inducing
treatment-limiting liver damage to the liver of the patient.
In particular embodiments, the present invention provides an improved
antihyperlipidemia composition of the oral type employing an effective
antihyperlipidemic amount of nicotinic acid, wherein the improvement
comprises compounding the nicotinic acid with from about 5% to about 50%
parts by weight of hydroxypropyl methylcellulose per hundred parts by weight
of tablet or formulation.
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The present invention also provides an orally administered antihyperlipidemia
composition which comprises from about 30% to about 90% parts by weight of
nicotinic acid; and, from about 5% to about 50% parts by weight of
hydroxypropyl methylcellulose.
The present invention also includes a method of treating hyperlipidemia in a
hyperlipidemic. The method comprises the steps of forming a composition
which comprises an effective antihyperlipidemic amount of nicotinic acid and
an amount of excipients to provide sustained release of drug. The method also
includes the step of orally administering the composition to the
hyperlipidemic
nocturnally.
A method of treating hyperlipidemia in a hyperlipidemic according to the
invention, comprises dosing the hyperlipidemic with an effective
antihyperlipidemic amount of nicotinic acid or compound metabolized to
nicotinic acid by the body. The dose is given once per day in the evening or
at
night, combined with a pharmaceutically acceptable carrier to produce a
significant reduction in total and LDL cholesterol as well as a significant
reduction in triglycerides and Lp(a), with a significant increase in HDL
cholesterol.
The above features and advantages of the present invention will be better
understood with reference to the following detailed description and examples.
It should also be understood that the particular methods and formulations
illustrating the present invention are exemplary only and not to be regarded
as
limitations of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
By way of illustrating and providing a more complete appreciation of the
present invention and many of the attendant advantages thereof, the following
detailed description and examples are given concerning the novel methods and
formulations.
The present invention employs nicotinic acid or a compound other than
nicotinic acid itself which the body metabolizes into nicotinic acid, thus
producing the same effect as described herein.
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The other compounds specifically include, but are not limited to the
following: nicotinyl alcohol
tartrate, d-glucitoi hexanicotinate, aluminum nicotinate, niceritrol and d, l-
alpha-tocopheryl
nicotinate. Each such compound will be collectively referred to hereinbelow by
"nicotinic acid."
As stated hereabove, nicotinic acid has been employed in the past for the
treatment of
hyperlipidemia, which condition is characterized by the presence of excess
fats such as cholesterol
and triglycerides, in the blood stream. According to the present invention, a
sustained release
composition of nicotinic acid is prepared as an example. By "sustained
release" it is understood
to mean a composition which when orally administered to a patient to be
treated, the active
ingredient will be released for absorption into the blood stream over a period
of time. For
exampled, it is preferred that in a dosage of about 1500 mi111grams
(hereinafter "mgs") of nicotinic
acid, approximately 100 percent of the nicotinic acid will be released into
the blood stream in
about 4 to about 24 hours.
The specified sustained releases composition according to the present
invention employs
an effective antihyperlipidemic amount of nicotinic acid. By "effective
antihyperlipidemic
amount" it is understood to mean an amount which when orally administered to a
patient to be
treated, will have a beneficial effect upon the physiology of the patient, to
include at least some
lowering of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and at
least some increase
in HDL cholesterol in the patient's blood stream. An exemplary effective
antihyperlipidemic
amount of nicotinic acid would be from about 250 mgs to about 3000 mgs of
nicotinic acid to be
administered according to the invention as will be more fully described
hereinbelow. This amount
will vary dependent upon a number of variables, including the psychological
needs of the patient
to be treated.
Preferably, there is also included in the sustained release composition
according to the
present invention, a swelling agent which is compounded with the nicotinic
acid, such that when
* ~ ~
CA 02574987 2007-02-02
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the composition is orally administered to the patient, the swelling agent will
swell over time in the
patient's gastrointestinal tract, and release the active nicotinic acid, or a
compound which
produces nicotinic acid into the gastrointestinal system for absorption into
the blood stream, over
a period of time As is known in the art, such swelling agents and amounts
thereof, may be
preselected in order to control the time release of the active ingredient.
Such swelling agents
include, but are not limited to, polymers such as sodium
carboxymethylcellulose and ethylcellulose
and waxes such as bees wax and natural materials such as gums and gelatins or
mixtures of any
of the above. Because the amount of the swelling agent will vary depending
upon the nature of
the agent, the time release needs of the patient and the like, it is preferred
to employ amounts of
the agent which will accomplish the objects of the invention.
An exemplary and preferred swelling agent is hydroxypropyl methylcellulose, in
an amount
ranging from about 5% to about 50% parts by weight per 100 parts by weight of
tablet or
formulation. The preferred example will ensure a sustained time release over a
period of
approximately 4-24 hours as demonstrated by in vitro dissolution techniques
known to the art
A binder may also be employed in the present compositions. While any known
binding
material is useful in the present invention, it is preferred to employ a
material such as one or more
of a group of polymers having the repeating unit of 1-ethenyl-2-pyrrolidinone.
These polymers
generally have molecular weights of between about 10,000 and 700,000, and are
also known as
"povidone".
Amounts of the binder material will of course, vary depending upon the nature
of the
binder and the amount of other ingredients of the composition. An exemplary
amount of
povidone in the present compositions would be from about 1% to about 5% by
weight of
povidone per 100 parts by weight of the total formulation.
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Processing aids such as lubricants, including stearic acid, may also be
employed, as is
known in the art. An exemplary amout of stearic acid in the present
compositions would be from
about 0.5% to about 2.0% by weight per 100 parts by weight of tablet or
formulation.
Examples of various embodiments of the present invention will now be further
illustrated
with reference to the following examples.
General Expgrimental
In order to demonstrate the effectiveness of the compositions and method of
the present
invention over known antihyperlipidemia compositions and methods heretofore
known in the art,
a number of substantially identical composition were prepared according to the
disclosure
hereinabove. The composition and ingredients and amounts are listed in TABLEI
A hereinbelow.
TABLE IA
Test Tablet Composition
Ingredient 375 mg 500 mQ 750 mg
Nicotinic Acid 375.0 500.0 750.0
Hyroxypropyl 188.7 203.0 204.7
methylcellulose
Povidone 12.9 17.2 25.9
Stearic Acid 5.8 7.3 9.9
TOTAL 582.4 mg 727.5 mg 990.5 mg
The ingredients were compounded together to form a tablet. More specifically,
Niaspan
once-daily tablets in accordance with the present invention utilize a
hydrophilic matrix controlled
drug delivery system. This is a dynamic system composed of polymer wetting,
polymer hydration
and polymer disintegration/dissolution. The mechanism by which drug release is
controlled
depends on, for example, initial polymer wetting, expansion of the gel layer,
tablet erosion and
niacin solubility. After initial wetting, the hydrophyllic polymer starts to
partially hydrate, forming
a gel layer. As water permeates into the tablet increasing the thickness of
the gel layer, drug
T Y I
CA 02574987 2007-02-02
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diffuses out of the gel layer. As the outer layer of the tablet becomes fully
hydrated it erodes. It
is believed that this erosion results in additional drug release. The
controlled release from this
matrix delivery system can be modified depending on the type and molecular
weight of hydrophilic
polymer used.
A Niaspan formulation consists of Niacin, Methocel E 1 OM Premium, Povidone
K90
and Hystrene 5016 (stearic acid) Methocel(K E l OM Premium is utilized as a
controlled-release
agent in the Niaspan formulation. Methocel is a partly 0-methylated and O-(2-
hydroxypropylated) cellulose and is available in several grades which vary in
terms of viscosity
and degree of substitution. Methocel is manufactured by Dow Chemical.
Povidone K90 is employed as a granulating/binding agent in a Niaspan
formulation.
Povidone is a synthetic polymer consisting of linear l-vinyl-2-pyrrolidone
groups, the degree of
polymerization of which results in polymers of various molecular weights, or
as indicated above.
It is characterized by its viscosity in aqueous solution, relative to that of
water, expressed as a K-
value, ranging from 10-120. Povidone K90 has an approximate molecular weight
of 1,000,000.
Povidone is a hygroscopic, water soluble material. Povidone K90 present in a
Niaspan
formulation is manufactured by ISP (International Specialty Products).
Hystrene 5016 is utilized
as an external lubricant in the Niaspan(g forumation. Hystrene 5016 is a
mixture of stearic acid
and palmitic acid. The content of stearic acid is not less than about 40.0%
and the sum of the two
acids is not less than about 90.0%. Hystrene 5016 is manufactured by Witco.
Refer to Table IB
for Niaspan forumlation details.
Qualitatively, the four tablet strength formulations are identical. The major
component
of each formulation is a granulated mixture of Niacin, Methocel E l OM and
Povidone K90. The
granulation process improves compression properties.
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TABLE IB
Niaspan Tablet Formulations
Niaspan Product 375mg Tablets 500mg Tablets .750mg Tablets 1000mg
Tablets
Formulation. Tablets
Niacin 64.4 70.5 77.4 83.1
Methocel E l OM 7.4 8.1 8.9 9.5
Premium
([ntragranular}
2.2 2.4 2.7 2.9
Povidone K90
Methocel E l OM
25.0 18.0 10.0 3.5
Prcmium
(Extragranular)
Hvstrenc 5016 1.0 1.0 1.0 1.0
(Stearic Acid)
Table weight, mg 582.5 709.5 968.6 1203.6
Niaspan formulations are presented in white caplet shape tablets. Caplet
dimensions
differ with respect to product strength. The 375mg and 500mg Niaspan tablets
are compressed
with tooling measuring approximately 0.687" in length x 0.281" by width. The
length and width
of the 750mg and 1000mg tooling measures approximately Ø750" x 0.320".
Target tablet weight
and hardness dictate thickness across the four Niaspan products. The
production of the
Niaspan tablets will now be described generally as set forth below.
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Niaspan Granulation Process Flow Chart
Raw Materials Process Flow EauiRment
Niacin Granulate High shear granulator
Povidone K90 (Littleford FM 130)
Methocel E 1 OM
(Intragranular)
Purfied Water
Dry Fluid bed drier
(Glatt fluid bed drier)
Parcel size reduction Mill
(Kemutec Betagrind)
Niaspan0 Granulation Process Description
Niaspan granulation raw materials are dispensed and granulated in a high
shear
granulator. The wet granules are sieved into a fluid bed drier and are dried.
When the drying
process is complete, the granules are milled. Milling ensures uniform particle
size distribution
throughout the Niaspan granulation.
Niaspan Tablet Process Flow Chart
Raw Materials Process Flow Equipment
Niasnan(k Tablet lilcnd
Mcthocel Blend Milled NiaspanQt~ granules Blcnder
E l OM with (Patterson-Kelley
(Extragranular) extragranular Methocel E l OM and V-Blender)
Hystrene
I lystrene 5016 5016
(Stearic acid)
Niaspan Tablc Manufacture
Compress Niaspant Tablet Blend Rotary tablet
press
Niasnan Tablet Process Description
A Niaspan tablet blend is manufactured by blending the Niaspan granulation,
extragranular Methocel El OM and Hystrene 5016. The quantities of each Niaspan
tablet blend
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component will depend on the particular Niaspan dose being manufactured
(refer to Table IB).
A Niaspan tablet blend is compressed to form NiaspanO tablets. Niaspan
tablet physical
properties will vary depending on the particular Niaspan dose being
manufactured.
Production of Niaspan tablets will now be discussed in greater detail. The
initial stage
of manufacturing is the same for all four tablet strengths of Niaspane (375,
500, 750 and
I000mg). One batch of NiaspanrD granulation is comprised of four individual
40.0kg units of
granulation which are processed separately, but under like conditions. The
four individual
granulations are sampled and tested individually and subsequently released for
blending. The base
granulation is not strength specific and may be used to manufacture any tablet
strength of
Niaspan .
The ingredients in the base granulation are set froth in Table IC below-
TABLE IC
Component Function Quantity per % per Quantity per
kilotzram kilogram 160.00 kg
granulation (kg) granulation batch (kg)
(%)
Niacin, IJSP I)rug Substancc
0.87 87.00 139.20
F I
Povidine, UPS Binder F 0.03 3.00 4.80
Methoccl USP, Controlled- 0,10 10.00 16.00
E l OM Premium Release Agent
CR Grade
Purified Water, Granulation 0.00" 0.00' 48
USP' Rcagcnt F
Total 160
'Purified Water, USP is used as granulation reagent and does not appear in the
finished
granulation.
Raw materials are quantatively dispensed into appropriately labeled double
polyethylene-
lined containers using calibrated scales. Purified Water, USP is dispensed
into an appropriate
vessel from which it is later pumped during the wet-massing operation.
A Littleford FM130 granulator is charged with approximately one half of the
Niacin, USP
required for the process unit (- 17.4 kg) followed by about 4.00kg of
Methocel, USP EIOM
Premium CR Grade; about 1.20kg of Povidine, USP; and the balance of the
Niacin, SP
(-17.40kg). The powder bed is dry mixed in the Littleford FM130 granulator,
with choppers on,
for approximately 1 minute. At the completion of the l-minute pre-mix cycle,
about 12.0 0.05kg
SUBSTITUTE SHEET (RULE 26)
r , I
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of Purified Water, USP are sprayed onto the powder bed at a rate of about
2.40f0.24kg/minute.
Immediately following the addition of the Purified Water, USP, the unit is
granulated for about
minutes.
The granulated unit is discharged into double polyethylene-lined containers
and then
5 manually loaded into a Glatt bowl while being passed through a #4 mesh
screen The Glatt bowl
is loaded into a Glatt TFO-60 fluid-bed drier with an inlet air temperature
setting of about
70 Cf5 C The unit is dried until a moisture level of < 1.0% is obtained as
determined using a
Computrac@ Moisture Analyzer, model MA5A. The dried granulation is discharged
into
appropriately labeled, double polyethylene-lined drums and reconciled.
The dried and reconciled granulation is passed through a Kemutec BetaGrind
mill
equipped with a 1.5mm screen and running at approximately 1500 RPM. The milled
granulation
is collected into appropriately labeled, double polyethylene-lined drums and
reconciled. The
milled granulation is sampled and tested by Quality Control and released prior
to further
processing.
The released granulation units are charged to a Patterson-Kelley 20 ft3 V-
blender after
which they are blended together for about 10 1 minutes and then discharged
to appropriately
labeled, double polyethylene-lined containers.
As stated above, Niaspan tablets are formulated from a common granulation
which is
blended with appropriate quantities of Methocel, USP E l OM Premium CR Grade
and Stearic
Acid, NF to achieve the final dosage formulation. Tables IA and IB describe
the formulation for
each Niaspan tablet strength, 375mg, 500mg, 750mg and 1000mg, respectively.
Two study groups consisting of eleven and fourteen patients each were formed.
Blood
samples were taken from the patients, and tested for total cholesterol, LDL
cholesterol,
triglycerides and HI?L cholesterol to establish baseline levels from which
fluctuations in these
lipids could be compared. The patients were then placed upon a regimen of the
above discussed
tablets, totaling approximately 1500 mg of nicotinic acid, once per day before
going to bed. After
eight weeks of this regimen, the patients were again tested for lipid
profiles. The results of tests
conducted at eight weeks, showing the changes in the lipid profiles as a
percentage change from
the baseline, are reported in the table hereinbelow. Positive numbers reflect
percentage increases
and negative numbers reflect percentage decreases in this table.
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TABLE II
Patient Study Lipid Profile Data
Pt. No. Tata -C LI)L-C, Apo R 'n w I.-C )I TI I,.-C
GROUI' A
1 -8.2 -12.0 NA -17.3 22.0 NA NA
2 -5 9 -27.0 NA -28,7 65.0 NA NA
3 -15.1 -13.0 NA -22.0 -9.1 NA NA
4 -3,3 -10.0 NA 61.6 3.8 NA NA
5 -16.5 -17.7 NA -28.8 11.1 NA NA
6 -12.4 -25.9 NA -42.0 51.6 NA NA
7 -24.2 -31.4 NA -39.4 12.5 NA NA
8 -6.7 -7.4 NA -42.4 18.8 NA NA
9 4.5 1.1 NA 7.2 9.2 NA NA
10 2.8 -0.2 NA -2.7 22,9 NA NA
11 -13.0 -9.4 NA -54_0 44.3 NA NA
Mean -8.9 -13,9 NA -18.9 23.0 NA NA
p-Valuc 0.0004-8.9 0.0001- 0.0371 0.0068
13.9
GROUP B
1 -19.2 -27.1 -24.4 -33.4 20.0 22.3 -81.9
2 -32.2 -35.7 -28.0 -60.4 4.3 3.2 -25.3
3 -21.4 -33.6 -35.6 -33.4 30.4 38.6 -17,4
4 -19.9 -24.6 -15.1 -20.8 9.6 16.1 -27.0
5 -3.3 -2.1 -29.4 -41.1 5.8 2.4 -22.4
6 PATIENT WITHDREW FROM STUDY
7 23.1 -32.6 -42.6 -58.6 49.2 68.9 -14.3
8 24.8 34.0 -28.4 5.5 6.5 -6.8 NA
9 10.1 12.0 -16.8 -11.6 20.7 -12.3 40.6
10 -2.9 -7.7 -28.0 -59.0 53.1 70.5 -41.2
11 -10.5 -18.8 -25.3 -53.4 31,8 39.7 NA
12 -20.0 -30.8 -30.4 11.7 21,1 25.0 -28.4
13 17.4 16.8 -17.5 -17.5 51.3 51.9 38.5
t ~ 1
CA 02574987 2007-02-02
= WO 98139002 PCT/US98/04590
-15-
TABLE II (Continued)
Patient Study Lipid Profile Data
I't. No. Total-C L L- ' Aoo B Tries HDI: C 1T1 )l.: C IM(a1
14 -9.4 -16.6 -32.0 -46.9 52.3 67.6 17.6
IviEAN -8.7 -12.8 -32.2 -27.2 25.3 30.1 -17.9
p-Value 0.0002 <0.0001 0.0001 <0.001 <0.0001 0.0002 <0.0188
Combined -8.7 -13.3 Gp i3 -26.1 25.3 (;p H Gp 13
p-Value 00002 <0.000I only <.0001 <0.0001 only onh
The data reported in Table II shows that the LDL levels in the Group A
patients had a
mean decrease of -13.9% and triglyceride decrease of -18.9% HDL cholesterol
levels, the
beneficial cholesterol, were raised by 23,0% in this Group. Similar results
were obtained with the
Group B patients. These studies demonstrate that dosing the sustained release
formulation during
the evening hours or at night provides reductions in LDL cholesterol levels
equal to immediate
release niacin on a milligram per milligram basis, but superior reductions in
trig)yceride reduction
when compared to sustained release formulations dosed during daytime hours on
a milligram per
milligram basis. Additionally, the increases in HDL cholesterol obtained from
dosing the
sustained release formulation during the evening or at night were +23.0% for
one group and
+25.3% for the other group. Dosing during the evening therefore provides
reduction in LDL
cholesterol plus significant decreases in triglycerides and increases in HDL
cholesterol with once-
a-day dosing.
Groups A and B were also tested for liver enzymes (AST, ALT and Alkaline
Phosphatase), uric acid and fasting glucose levels at the start of the study
described hereinabove
(to form a baseline) and at two, four and eight week intervals. The results of
these tests are listed
in TABLES III-VII hereinbelow.
CA 02574987 2007-02-02 WO 98/39002 PCT/US98/04590
-16-
TABLE III
THE EFFECT OF NIASPAN THERAPY ON AST (SGOT) LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
rt# ai i e 2 Wks. 4 Wks. 8 Wks. Reference
Range
GROUI' A
1 28 29 25 24 0-5(1
2 24 25 24 26 0-50
3 17 19 22 21 0-50
4 14 16 15 17 0-50
5 22 NA 32 52 0-5(1
6 21 17 17 14 0-50
7 17 17 14 18 0-50
8 20 21 22 22 0-50
9 16 16 17 20 0-50
10 18 21 21 25 0-50
11 21 21 22 21 0-50
GROUP B
1 23 25 38 33 0-50
2 20 20 21 21 050
3 15 20 18 19 0-50
4 25 22 28 26 0-50
5 23 21 17 18 0-50
6 PATI1riNT WITI ID12EW DUE TO FLUSHING
7 21 18 18 19 0-50
8 18 19 18 19 0-50
9 15 16 18 15 0-50
10 16 15 19 28 0-50
11 20 22 24 28 0-50
12 23 25 28 22 0-50
13 20 15 20 19 0-50
r ~ ~
CA 02574987 2007-02-02
WO 98/39002 PCT/US98/04590
-17-
TABLE III (Continued)
THE EFFECT OF NIASPAN THERAPY ON AST (SGOT) LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
~t# aa li e 2 Wks. 4 Wks. 8 Wks. Rcferencc
RaaQe
14 18 25 20 18 0-50
Combincd Mcan 19.8 20 4 208 21.1
Change From +3.0% +5.1 % +6.6%
Baseline
Level of Signiticance: p=0.4141
TABLE IV
THE EFFECT OF NIASPAN THERAPY ON ALT (SGPT) LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
Pt# Baseline 2 Wks, 4'Wks= 8 Wks. Reference
RanQe
GROUP A
1 32 28 39 30 0-55
2 24 25 23 26 0-55
3 18 23 30 30 0-55
4 7 13 14 14 0-55
5 14 NA 43 46 0-55
6 22 11 14 10 0-55
7 9 7 11 7 0-55
8 16 18 23 21 0-55
9 14 17 20 14 0-55
10 14 15 17 19 0-55
11 18 18 20 16 0-55
CA 02574987 2007-02-02, = WO 98/39002 PCT/US98/04590
-18-
TABLE IV (Continued)
THE EFFECT OF NIASPAN THERAPY ON ALT (SGPT) LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
15 Pt# Baseline 2 Wks. 4 Wks. 8 Wks. Reference
$anQe
GROUP B
1 16 17 27 29 0-55
2 16 14 15 22 0-55
3 13 21 13 16 0-55
4 23 20 26 17 055
5 21 23 17 15 0-55
6 PATIENT WITHDREW DUE TO FLUSHING
7 21 16 18 21 0-55
8 18 20 17 18 0-55
9 11 5 11 8 0-55
10 8 10 14 17 0-55
11 17 12 18 16 0-55
12 14 18 20 16 0-55
13 14 NA 11 10 0-55
14 23 23 19 19 0-55
Combined 17.7 17,5 19.3 18.2
Mean
Change -1.1% 9.0% +2, 8%
From
Baseline
Level of Significance: p=0.3424
T ~ r
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WO 98/39002 PCTIUS98/04590
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TABLE V
THE EFFECT OF NIASPAN THERAPY
ON ALKALINE PHOSPHATASE LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
Baseline 2 Wks 4 Wks 8 Wks Reference
I3apg,!
GROUP A
1 52 56 57 55 20-140
2 103 100 89 102 20-140
3 54 45 53 51 20-140
4 70 68 71 91 20-140
5 77 NA 74 81 20-140
6 55 48 49 51 20-140
7 72 71 79 75 20-140
8 55 49 47 50 20-140
9 53 55 56 45 20-140
10 74 73 75 75 20-140
11 18 18 20 16 20-140
GROUP B
1 73 67 89 95 20-140
2 82 64 72 71 20-140
3 73 69 72 82 20-140
4 37 36 37 38 20-140
5 65 53 54 61 20-140
6 PATIENT WITHDREW DUE TO FLUSHING
7 64 58 58 58 20-140
8 79 78 65 73 20-140
9 94 92 103 93 20-140
CA 02574987 2007-02-02, = WO 98/39002 PCT/US98104590
- 20 -
TABLE V (Continued)
THE EFFECT OF NIASPAN THERAPY
ON ALKALINE PHOSPHATASE LEVELS (U/L)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
Pt# Baseline 2 Wks gWks 8 Wks Reference
Range
69 67 70 65 20-140
11 59 67 63 72 20-140
12 65 59 59 63 20-140
13 64 68 66 64 20-140
5 14 72 61 59 64 20-140
Combined 66,5 61.5 63,3 65.8
Mean
Change -6.1% -3.4% +0.005%
From
10 Baseline
Level of Significance: p=0.0236
r T r
CA 02574987 2007-02-02
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TABLE VI
THE EFFECT OF NIASPAN THERAPY ON URIC ACID LEVELS (mg/dL)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
P,~# Baseline 2 Wks. 4 Wks. 8 Wks. Reference
Range
GROUP A
1 5.2 5.0 4.8 4.3 4.0-8.5
2 4.0 4.6 4.5 6.2 2.5-7.5
3 6.3 7.0 6.5 6.2 4.0-8.5
4 3.1 4.6 4.2 3.8 2.5-7.5
5 3.4 NA 3.3 4.2 2.5-7.5
6 6.6 5.5 5.6 4.7 4.0-8.5
7 3.8 4.5 4.3 4.9 2.5-7.5
8 4.4 3.8 5.1 4.5 2.5-7.5
9 3,9 4,5 4.6 3.5 2.5-7.5
10 2.6 2.9 2.8 2.7 2.5-7.5
11 4.7 5.5 5.2 5.3 2.5-7.5
GROUP B
1 3.7 4.2 4.7 3.5 2.5-7.5
2 2.8 3,5 3.6 2.3 4.0-8.5
3 4.2 5.3 5.5 5.3 2.5-7.5
4 4.7 3.9 5.1 3.6 4_0-8.5
5 3.7 4.1 4.1 3.8 2.5-7.5
6 PATIENT WITHDREW DUE TO FLUSHING
7 5.8 6.6 6.6 6.8 2.5-7.5
8 4.7 4.3 5.4 5.6 2.5-7.5
9 3.7 4.6 5,1 3.8 2.5-7.5
CA 02574987 2007-02-02,
=
WO 98/39002 PCT/US98/04590
-22-
TABLE VI (Continued)
THE EFFECT OF NIASPAN THERAPY ON URIC ACID LEVELS (mg/dL)
(1500 mgs dosed once-a-day at night)
(n = 28)
Weeks of Therapy With Niaspan
Baseline 2 Wks. 4 Wks. g Wks= Reference
Range
4.2 5.0 4.4 8.5 2.5-7.5
11 1.9 3.0 2.8 5.0 2.5-7.5
12 5.6 5.4 6.2 5.6 4.0-8.5
13 4.2 4.6 4.6 5.3 2.5-7.5
5 14 5.5 5.4 6.1 5.3 2.5-7.5
Combined 4.54 4.82 4.92 4.86 *p=0.3450
Mean
Change +6.2% +8.4% +7.0%
From
10 Baseline
*Level of Significance: p=0.3450
t T '
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WO 98/39002 PCT/US98/04590
-23-
TABLE VII
THE EFFECT OF NIASPAN THERAPY
ON FASTING GLUCOSE LEVELS (mg/dL)
(n = 28)
Weeks of Therapy With Niaspan
Pt# Baseline 2 Wks 4 Wks= 8 Wks Reference
Range
GROUP A
1 114 122 123 110 70-115
2 101 105 107 101 80-125
3 99 98 109 103 70-115
4 100 118 94 94 80-125
5 89 NA 82 103 80-125
6 97 103 94 107 70-115
7 85 107 100 94 80-125
8 98 107 103 101 80-125
9 97 97 100 110 80-125
10 94 101 111 97 70-115
11 102 103 95 95 80-125
GROUP B
1 101 97 83 99 70-115
2 90 95 96 89 80-125
3 96 98 95 97 70-115
4 116 139 113 125 80-125
5 88 98 91 95 70-115
6 PATIENT WITHDREW DUE TO FLUSHING
7 106 114 118 117 70-115
8 95 106 106 108 70-115
9 81 92 84 92 70-115
10 108 117 122 105 70-115
CA 02574987 2007-02-02,
WO 98/39002 PCTIUS98/04590
-24-
TABLE VII (Continued)
THE EFFECT OF NIASPAN THERAPY
ON FASTING GLUCOSE LEVELS (mg/dL)
(n = 28)
Weeks of Therapy With Niaspan
g~# Baseline 2 Wks 4 Wks. 8 Wks Reference
Ra=
1] 85 106 106 108 70-115
12 92 89 101 86 80-125
13 99 105 94 100 70-125
14 100 108 84 107 70-125
Combined 98.4 105.8 101.6 102.3
Mean
Change From +7.5% +3.3% +4.0%
Baseline
Level of Significance: p=0.0021
In order to provide a comparison between the state of the art prior to the
present
invention, and in order to quantify the magnitude of the improvement that the
invention provides
over the prior art, another study was conducted. This study included 240
patients dosed
according to the present invention as described hereinabove. Compared to this
group was the
group of patients studied by McKenney et al., as reported hereinabove. The
results of this study
are reported in TABLE VIII hereinbelow.
T 1 1
TABLE VIII ~
A Comparison of Changes in Liver Function Tests
DOSE
r 0 - 500 1000 1500 2000 2500 3000 ~ TOTAL
McK
N ac'in' ermey Sr' F
AST 23.8 27,9 40.4 36.6 56.5 na 1970
% 117 170 154 237 na 408 v
Invenlion Dosage 00
AST F 24.3 na 23.7 173 26.6 27 6 27 8 ~ o
% ~-- na 98 113 109 114 114 o
0
~~e~nney SR
ALT 25.6 29.5 36.3 39.0 59. t NA 1000
% ~- 115 142 152 231 NA 391
Invention Dosage ~- ~ r
ALT 21,4 na 18.7 22.6 21.3 22.4 218
% -- na 87 106 100 105 1102
McKenney SR
Niacin a
ALK 95 95 106 105 136 na l135
~
TABLE VIII (Continued)
A Comparison of Changes in Liver Function Tests
DOSE
0 500 1000 1500 2000 2500 3000 TOTAL
% F 100 112 111 143 na 142
Invention Dosage
I ALK 74.7 na 73 9 76.1 73.4 767 780
0
% ~- na 99 102 98 ~ 103 104 ~
.P.
Mc){~nney SR t
Drop F0 2 2 7 na 7 18
n 23 no,
% -- 0 9 9 30 na 130 78
Invention Dosage I
Drop ~- -- 0 0 0 0 0 0
n F- -- 26 67 97 35 15 240
J % ~' -- ~ 0 0 0 0 l0 0
I -- -- 15 46 77 31 15 184 'tl
year
1 ~ -- 58 69 79 89 100 77
year
- ~o
o -
CA 02574987 2007-02-02
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-27-
Dosed twice-per-day as described in "A Comparison of the Efficacy and Toxic
Effects of
Sustained - vs Immediate - Release Niacin in Hypercholesterolemic Patients" by
McKenney et al.
loumal of the American Medical Association, March 2, 1994; Vol. 271, No. 9,
pages 672-677.
b SR is "sustained release"
Dosed once-per-day at night
The results of the comparison of the studies reported in Table VIII show that
the control
group (the McKenney group) had 18 of 23, or 78 percent of the patients therein
drop out of the
test because of an increase in their respective liver function tests. The
patients withdrew at the
direction of the investigator. In comparison, a group of 240 patients treated
according to the
present invention had zero patients drop out, based upon the same criteria for
withdrawal. The
test results reported above indicate that this sustained release dosage form
caused no elevation
in liver function tests (i.e., no liver damage), no elevations in uric acid
and only a small, 7.5%
increase in fasting glucose levels which in fact decreased during continued
therapy.
Thus it should be evident that the compositions and method of the present
invention are
highly effective in controlling hyperlipidemia in hyperlipidemics, by reducing
the levels of LDL
cholesterol, triglyceride and Lp(a) while increasing HDL cholesterol levels.
The present invention
is also demonstrated not to cause elevations in liver function tests, uric
acid or glucose levels for
the hyperlipidemics.
Based upon the foregoing disclosure, it should now be apparent that the use of
the
compositions and methods described herein will carry out the objects set forth
hereinabove. It
is, therefore, to be understood that any variations in sustained release
formulation evident fall
within the scope of the claimed invention and thus, the selection of specific
component elements
can be determined without departing from the spirit of the invention herein
disciosed and
described. In particular, sustained release excipients, binders and processing
aids according to
the present invention are not necessarily limited to those exemplified
hereinabove. Thus, the
scope of the invention shall include all modifications and variations that may
fall within the scope
of the attached claims.
