U.S. patent application number 13/105115 was filed with the patent office on 2011-10-06 for nicotinic acid compositions for treating hyperlipidemia and related methods therefor.
Invention is credited to David J. Bova.
Application Number | 20110245300 13/105115 |
Document ID | / |
Family ID | 29783152 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110245300 |
Kind Code |
A1 |
Bova; David J. |
October 6, 2011 |
NICOTINIC ACID COMPOSITIONS FOR TREATING HYPERLIPIDEMIA AND RELATED
METHODS THEREFOR
Abstract
An orally administered antihyperlipidemia composition according
to the present invention includes from about 250 to about 3000
parts by weight of nicotinic acid, and from about 5 to about 50
parts by weight of hydroxypropyl methylcellulose. Also, a method of
treating hyperlipidemia in a hyper lipidemic having a substantially
periodic physiological loss of consciousness, includes the steps of
forming a composition having an effective antihyperlipidemic amount
of nicotinic acid and a time release sustaining amount of a
swelling agent. The method also includes the step of orally
administering the composition to the hyperlipidemic once per day
"nocturnally," that is in the evening or at night.
Inventors: |
Bova; David J.; (Chapel
Hill, NC) |
Family ID: |
29783152 |
Appl. No.: |
13/105115 |
Filed: |
May 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12187960 |
Aug 7, 2008 |
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13105115 |
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11757965 |
Jun 4, 2007 |
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12187960 |
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10444145 |
May 23, 2003 |
7998506 |
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11757965 |
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09478325 |
Jan 6, 2000 |
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10444145 |
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08814974 |
Mar 6, 1997 |
6129930 |
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09478325 |
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08368378 |
Jan 14, 1995 |
6080428 |
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08814974 |
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08124392 |
Sep 20, 1993 |
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08368378 |
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Current U.S.
Class: |
514/356 |
Current CPC
Class: |
A61P 7/00 20180101; A61K
31/44 20130101; A61P 3/06 20180101; A61K 9/2027 20130101; A61K
9/2077 20130101; A61K 9/2054 20130101; A61K 31/455 20130101; A61P
3/10 20180101 |
Class at
Publication: |
514/356 |
International
Class: |
A61K 31/455 20060101
A61K031/455; A61P 3/06 20060101 A61P003/06 |
Claims
1-12. (canceled)
13. A method for treating hyperlipidemia in a hyperlipidemic, the
method comprising the steps of: dosing the hyperlipidemic with a
sustained release oral solid dosage form comprising about 500 mg
nicotinic acid once per day and wherein the hyperlipidemic's total
cholesterol, LDL cholesterol, triglycerides and Lp(a) are reduced
and the hyperlipidemic's HDL cholesterol is increased.
14. The method according to claim 13, wherein the hyperlipidemic is
dosed at night or in the evening.
15. A method for treating hyperlipidemia in a hyperlipidemic, the
method comprising the steps of: dosing the hyperlipidemic with a
sustained release oral solid dosage form comprising about 750 mg
nicotinic acid once per day and wherein the hyperlipidemic's total
cholesterol, LDL cholesterol, triglycerides and Lp(a) are reduced
and the hyperlipidemic's HDL cholesterol is increased.
16. The method according to claim 15, wherein the hyperlipidemic is
dosed at night or in the evening.
17. A method for treating hyperlipidemia in a hyperlipidemic, the
method comprising the steps of: dosing the hyperlipidemic with a
sustained release oral solid dosage form comprising about 1000 mg
nicotinic acid once per day and wherein the hyperlipidemic's total
cholesterol, LDL cholesterol, triglycerides and Lp(a) are reduced
and the hyperlipidemic's HDL cholesterol is increased.
18. The method according to claim 17, wherein the hyperlipidemic is
dosed at night or in the evening.
19. A method for treating hyperlipidemia in a hyperlipidemic, the
method comprising the steps of: dosing the hyperlipidemic with a
sustained release oral solid dosage form comprising about 2000 mg
nicotinic acid once per day and wherein the hyperlipidemic's total
cholesterol, LDL cholesterol, triglycerides and Lp(a) are reduced
and the hyperlipidemic's HDL cholesterol is increased.
20. The method according to claim 19, wherein the hyperlipidemic is
dosed at night or in the evening.
21. The method according to claim 13 or 14, wherein the sustained
release oral solid dosage form is administered to the
hyperlipidemic after the ingestion of food by said hyperlipidemic
or as said hyperlipidemic lies down to go to sleep.
22. The method according to claim 15 or 16, wherein the sustained
release oral solid dosage form is administered to the
hyperlipidemic after the ingestion of food by said hyperlipidemic
or as said hyperlipidemic lies down to go to sleep.
23. The method according to claim 17 or 18, wherein the sustained
release oral solid dosage form is administered to the
hyperlipidemic after the ingestion of food by said hyperlipidemic
or as said hyperlipidemic lies down to go to sleep.
24. The method according to claim 19 or 20, wherein the sustained
release oral solid dosage form is administered to the
hyperlipidemic after the ingestion of food by said hyperlipidemic
or as said hyperlipidemic lies down to go to sleep.
Description
RELATED PATENT APPLICATIONS
[0001] This application for U.S. patent is a U.S.C., Title 35,
.sctn.111(a) application which is a continuation of U.S. patent
application Ser. No. 08/368,378 filed Jan. 14, 1995, which is a
continuation-in-part of U.S. patent application Ser. No.
08/124,392, filed Sep. 20, 1993.
FIELD OF THE INVENTION
[0002] 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.
BACKGROUND
[0003] 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".
[0004] 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 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
often occurs in the hyperlipidemics to whom the compound is
administered.
[0005] 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 magnesium salts as
reported in U.S. Pat. No. 4,911,917. These materials have been
reported to avoid or reduce the cutaneous flushing side effect
commonly associated with nicotinic acid treatment.
[0006] 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 NICOBID.TM. capsules
(Rhone-Poulenc Rorer), ENDUR-ACIN.TM. (Innovite Corporation) and
U.S. Pat. No. 5,126,145 which describes a sustained release niacin
formulation containing two different types of hydroxypropyl
methylcellulose and a hydrophobic component.
[0007] 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 reduction in triglycerides (-2%
for the sustained release versus -38% for the immediate release)
and lower increase in HDL cholesterol, represented as HDL.sub.2
particles which are known by the an to be most beneficial (-5% for
the sustained release versus +37% for the immediate release).
[0008] 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.
[0009] In a recent edition of the JOURNAL OF THE AMERICAN MEDICAL
ASSOCIATION (JAMA), an article 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 Hypercholesterolemic Patients", McKenney et al., JAMA,
Vol. 271, No. 9, Mar. 2, 1994, page 672. The article presented a
study of twenty-three patients. Of that number, 18 or 78 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."
[0010] 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.
[0011] 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, 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
[0012] 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.
[0013] It is therefore an object of the present invention to
provide a composition of nicotinic acid or any compound which is
metabolized by the body to form nicotinic acid for treating
hyperlipidemia.
[0014] It is another object of the present invention to provide a
composition as above, which has a time release sustaining
characteristic.
[0015] It is yet another object of the present invention to provide
a method for employing a composition as above, for treating
hyperlipidemia, which results in little or no liver damage.
[0016] At least one or more of the foregoing objects, 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 and claimed.
[0017] In general 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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
[0022] 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.
[0023] 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.
The other compounds specifically include, but are not limited to
the following: nicotinyl alcohol tartrate, d-glucitol
hexanicotinate, aluminum nicotinate, niceritrol and
d,1-alpha-tocopheryl nicotinate. Each such compound will be
collectively referred to hereinbelow by "nicotinic acid."
[0024] As stated hereinabove, 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 example, it is
preferred that in a dosage of about 1500 milligrams (hereinafter
"mgs") of nicotinic acid, approximately 100 percent of the
nicotinic acid will be released to the blood stream in about 4 to
about 24 hours.
[0025] The specific sustained release 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.
[0026] 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 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.
[0027] 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.
[0028] 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".
[0029] 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.
[0030] Processing aids such as lubricants, including stearic acid,
may also be employed, as is known in the art. An exemplary amount
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.
[0031] Examples of various embodiments of the present invention
will now be further illustrated with reference to the following
examples.
[0032] General Experimental
[0033] 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
ingredients and amounts are listed in TABLE IA hereinbelow.
TABLE-US-00001 TABLE IA Test Tablet Composition Ingredient 375 mg
500 mg 750 mg Nicotinic Acid 375.0 500.0 750.0 Hyroxypropyl
methylcellulose 188.7 203.0 204.7 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
[0034] The ingredients were compounded together to form a tablet.
More specifically, NIASPAN.RTM. 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
hydrophilic polymer starts to partially hydrate, forming a gel
layer. As water permeates into the tablet increasing the thickness
of the gel layer, drug 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.
[0035] A NIASPAN.RTM. formulation consists of Niacin, METHOCEL.RTM.
E10M Premium, Povidone K90 and HYSTRENE.RTM. 5016 (stearic acid).
METHOCEL.RTM. E10M Premium is utilized as a controlled-release
agent in the NIASPAN.RTM. formulation. METHOCEL.RTM. is a partly
O-methylated and O-(2-hydroxypropylated) cellulose and is available
in several grades which vary in terms of viscosity and degree of
substitution. METHOCEL.RTM. is manufactured by Dow Chemical.
[0036] Povidone K90 is employed as a granulating/binding agent in a
NIASPAN.RTM. formulation. Povidone is a synthetic polymer
consisting of linear 1-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.RTM.
formulation is manufactured by ISP (International Specialty
Products). HYSTRENE.RTM. 5016 is utilized as an external lubricant
in the NIASPAN.RTM. formulation. HYSTRENE.RTM. 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.RTM. 5016 is manufactured by Witco. Refer to
Table IB for NIASPAN.RTM. formulation details.
[0037] Qualitatively, the four tablet strength formulations are
identical. The major component of each formulation is a granulated
mixture of Niacin, METHOCEL.RTM. E10M and Povidone K90. The
granulation process improves compression properties.
TABLE-US-00002 TABLE IB 375 mg 500 mg 750 mg 1000 mg NIASPAN .RTM.
Product Tablets Tablets Tablets Tablets Formulation, %/Tablet
Niacin 64.4 70.5 77.4 83.1 METHOCEL .RTM. E10M 7.4 8.1 8.9 9.5
Premium (Intragranular) 2.2 2.4 2.7 2.9 Povidone K90 METHOCEL .RTM.
E10M Premium 25.0 18.0 10.0 3.5 (Extragranular) HYSTRENE .RTM. 5016
1.0 1.0 1.0 1.0 (Stearic Acid) Tablet weight, mg 582.5 709.5 968.6
1203.6
[0038] NIASPAN.RTM. formulations are presented in white caplet
shape tablets. Caplet dimensions differ with respect to product
strength. The 375 mg and 500 mg NIASPAN.RTM. tablets are compressed
with tooling measuring approximately 0.687'' in
length.times.0.281'' by width. The length and width of the 750 mg
and 1000 mg tooling measures approximately 0.750''.times.0.320''.
Target tablet weight and hardness dictate thickness across the four
NIASPAN.RTM. products. The production of the NIASPAN.RTM. tablets
will now be described generally as set forth below.
[0039] NIASPAN.RTM. Granulation Process Description
[0040] NIASPAN.RTM. 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.RTM. granulation.
[0041] NIASPAN.RTM. Tablet Process Description
[0042] A NIASPAN.RTM. tablet blend is manufactured by blending the
NIASPAN.RTM. granulation, extragranular METHOCEL.RTM. E10M and
HYSTRENE.RTM. 5016. The quantities of each NIASPAN.RTM.tablet blend
component will depend on the particular NIASPAN.RTM. dose being
manufactured (refer to Table IB). A NIASPAN.RTM. tablet blend is
compressed to form NIASPAN.RTM. tablets. NIASPAN.RTM. tablet
physical properties will vary depending on the particular
NIASPAN.RTM. dose being manufactured.
[0043] Production of NIASPAN.RTM. tablets will now be discussed in
greater detail. The initial stage of manufacturing is the same for
all four tablet strengths of NIASPAN.RTM. (375, 500, 750, and 1000
mg). One batch of NIASPAN.RTM. granulation is comprised of four
individual 40.0 kg 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.RTM..
[0044] The ingredients in the base granulation are set forth in
Table IC below:
TABLE-US-00003 TABLE IC Quantity per % per Quantity kilogram
kilogram per granulation granulation 160.00 kg Component Function
(kg) (%) batch (kg) Niacin USP Drug 0.87 87.00 139.20 Substance
Povidone USP Binder 0.03 3.00 4.80 METHOCEL .RTM. Controlled- 0.10
10.00 16.00 USP, E10M Release Premium CR Agent Grade Purified
Water, Granulation 0.00* 0.00* 48.00 USP* Reagent Total 160.00
*Purified Water, USP is used as a granulation reagent and does not
appear in the finished granulation.
[0045] 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.
[0046] A Littleford FM130 granulator is charged with approximately
one half of the Niacin, USP required for the process unit
(.about.17.4 kg) followed by about 4.00 kg of METHOCEL.RTM., USP
E10M Premium CR Grade; about 1.20 kg of Povidone, USP; and the
balance of the Niacin, SP (.about.17.40 kg). The powder bed is dry
mixed in the Littleford FM130 granulator, with choppers on, for
approximately 1 minute. At the completion of the 1-minute pre-mix
cycle, about 12.0.+-.0.05 kg of Purified Water, USP are sprayed
onto the powder bed at a rate of about 2.40.+-.0.24 kg/minute.
Immediately following the addition of the Purified Water, USP, the
unit is granulated for about 5 minutes.
[0047] The granulated unit is discharged into double
polyethylene-lined containers and then 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.degree. C..+-.5.degree. C. The unit
is dried until a moisture level of .ltoreq.1.0% is obtained as
determined using a COMPUTRACT.RTM. Moisture Analyzer, model MA5A.
The dried granulation is discharged into appropriately labeled,
double polyethylene-lined drums and reconciled.
[0048] The dried and reconciled granulation is passed through a
KEMUTEC BETAGRIND.RTM. mill equipped with a 1.5 mm 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.
[0049] The released granulation units are charged to a
Patterson-Kelley 20 ft.sup.3 V-blender after which they are blended
together for about 10.+-.1 minutes and then discharged to
appropriately labeled, double polyethylene-lined containers.
[0050] As stated above, NIASPAN.RTM. tablets are formulated from a
common granulation which is blended with appropriate quantities of
METHOCEL.RTM., USP E10M Premium CR Grade and Stearic Acid, NF to
achieve the final dosage formulation. Tables IA and IB describe the
formulation for each NIASPAN.RTM. tablet strength, 375 mg, 500 mg,
750 mg, and 1000 mg, respectively.
[0051] 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
HDL 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 the 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.
TABLE-US-00004 TABLE II Patient Study Lipid Profile Data Pt. No.
Total-C LDL-C ApoB Trigs HDL-C HDL.sub.2-C Lp(a) GROUP 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-Value 0.0004
0.0001 0.0371 0.0068 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 .sup. 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 14 -9.4 -16.6 -32.0 -46.9 52.3 67.6 17.6
Mean -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 B -26.1 25.3 Gp B Gp B p-Value 0.0002 <0.0001 only
<.0001 <0.0001 only only
[0052] 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.sub.2 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 triglyceride reductions 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.
[0053] 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.
TABLE-US-00005 TABLE III THE EFFECT OF NIASPAN .RTM. THERAPY ON AST
(SGOT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28)
Weeks of Therapy with NIASPAN .RTM. Reference Pt# Baseline 2 Wks. 4
Wks. 8 Wks. Range GROUP A 1 28 29 25 24 0-50 2 24 25 24 26 0-50 3
17 18 22 21 0-50 4 14 16 15 17 0-50 5 22 NA 32 52 0-50 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 0-50 3 15 20 18 19 0-50 4 25 22 25 26 0-50 5 23 21 17
18 0-50 6 PATIENT WITHDREW 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 14 18 25 20 18 0-50
Combined Mean 19.8 20.4 20.8 21.1 Change From +3.0% +5.1% +6.6%
Baseline Level of Significance: p = 0.4141
TABLE-US-00006 TABLE IV THE EFFECT OF NIASPAN .RTM. THERAPY ON ALT
(SGPT) LEVELS (U/L) (1500 mgs dosed once-a-day at night) (n = 28)
Weeks Of Therapy With NIASPAN .RTM. Reference Pt# Baseline 2 Wks. 4
Wks. 8 Wks. Range 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 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 0-55 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 Mean
17.7 17.5 19.3 18.2 Change From -1.1% 9.0% +2.8% Baseline Level of
Significance: p = 0.3424
TABLE-US-00007 TABLE V THE EFFECT OF NIASPAN .RTM. THERAPY ON
ALKALINE PHOSPHATASE LEVELS (U/L) (1500 mgs dosed once-a-day at
night) (n = 28) Weeks Of Therapy With NIASPAN .RTM. Reference Pt#
Baseline 2 Wks. 4 Wks. 8 Wks. Range 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 10 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 14 72 61 59 64 20-140
Combined Mean 66.5 61.5 63.3 65.8 Change From -6.1% -3.4% +0.005%
Baseline Level of Significance: p == 0.0236
TABLE-US-00008 TABLE VI THE EFFECT OF NIASPAN .RTM. THERAPY ON URIC
ACID LEVELS (mg/dL) (1500 mgs dosed once-a-day at night) (n = 28)
Weeks Of Therapy With NIASPAN .RTM. Reference Pt# Baseline 2 Wks. 4
Wks. 8 Wks. 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 10 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 14 5.5 5.4 6.1 5.3 2.5-7.5 Combined Mean 4.54 4.82 4.92
4.86 *p = 0.3450 Change From +6.2% +8.4% +7.0% Baseline *Level of
Significance: p == 0.3450
TABLE-US-00009 TABLE VII THE EFFECT OF NIASPAN .RTM. THERAPY ON
FASTING GLUCOSE LEVELS (mg/dL) (1500 mgs dosed once-a-day at night)
(n = 28) Weeks Of Therapy With NIASPAN .RTM. Reference Pt# Baseline
2 Wks. 4 Wks. 8 Wks. 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
92 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 11 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 Mean 98.4
105.8 101.6 102.3 Change From +7.5% +3.3% +4.0% Baseline Level of
Significance: p = 0.0021
TABLE-US-00010 TABLE VIII A Comparison of Changes in Liver Function
Tests DOSE: 0 500 1000 1500 2000 2500 3000 TOTAL McKenney SR.sup.b
Niacin.sup.a AST 23.8 27.9 40.4 36.6 56.5 NA 97 % -- 117 170 154
237 NA 408 Invention Dosage.sup.c AST 24.3 NA 23.7 27.5 26.6 27.6
27.8 % -- NA 98 113 109 114 114 McKenney SR Niacin ALT 25.6 29.5
36.3 39.0 59.1 NA 100.0 % -- 115 142 152 231 NA 391 Invention
Dosage ALT 21.4 NA 18.7 22.6 21.3 22.4 21.8 % -- NA 87 106 100 105
102 McKenney SR Niacin ALK 95 95 106 105 136 NA 135 % -- 100 112
111 143 NA 142 Invention Dosage ALK 74.7 NA 73.9 76.1 73.4 76.7 78
% -- NA 99 102 98 103 104 McKenney SR Niacin Drop -- 0 2 2 7 NA 7
18 n -- -- -- -- -- -- -- 23 % -- 0 9 9 30 NA 30 78 Invention
Dosage Drop -- -- 0 0 0 0 0 0 n -- -- 26 67 97 35 15 240 % -- -- 0
0 0 0 0 0 1 year -- -- 15 46 77 31 15 184 1 year -- -- 58 69 79 89
100 77 .sup.aDosed 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. Journal
of the American Medial Association. Mar. 2, 1994; 271, No. 9, pages
672-677. .sup.bSR is "sustained release" .sup.cDosed once-per-day
at night
[0054] 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.
[0055] 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 tests 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.
[0056] 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.sub.2
cholesterol levels. The present invention is also demonstrated not
to cause elevations in liver function tests, uric acid or glucose
levels for the hyperlipidemics.
[0057] 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 disclosed 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 my fall within the scope of the
attached claims.
* * * * *