CA2574987A1 - Nicotinic acid compositions for treating hyperlipidemia and related methods therefor - Google Patents

Abstract

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, has use in daily treatment of hyperlipidemia in a patient without inducing treatment-limiting liver damage, the formulation comprises a compressed blend of nicotinic acid in a hydrophilic matrix which controls delivery of the nicotinic acid;
the compressed blend comprises agglomerates and contains an effective antihyperlipidemic amount of nicotinic acid, a swelling agent, a granulation binder, and a lubricant; the swelling agent is a hydrophilic 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 the swelling agent of the hydophilic matrix provides controlled sustained release of the nicotinic acid from the hydophilic matrix, whereby the blend forms an oral sustained release solid dosage form in which the sustained release is without inducing treatment-limiting liver damage to the liver of the patient.

Description

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 DOCSMTL: 2304390\1 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 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, 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.

-4a -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;

- 4b -(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.

DOCSMTL: 2231678\I

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.

DOCSMTL: 223167811 WO 98/39002 PC'T/US98/04590 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 * ~ ~

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.

CA 02574987 2007-02-02, 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

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 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.

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.

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 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

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.

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 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 = WO 98139002 PCT/US98/04590 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.

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 5 22 NA 32 52 0-5(1 GROUP B

6 PATI1riNT WITI ID12EW DUE TO FLUSHING

r ~ ~

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 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

CA 02574987 2007-02-02, = WO 98/39002 PCT/US98/04590 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

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 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

GROUP B

CA 02574987 2007-02-02, = WO 98/39002 PCT/US98104590 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 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 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 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, =

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 ' 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

GROUP B

CA 02574987 2007-02-02, 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 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.

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 ~~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

% F 100 112 111 143 na 142 Invention Dosage I ALK 74.7 na 73 9 76.1 73.4 767 780 % ~- 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 -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.

Claims (10)

1. 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 hydrophilic 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.

2. A formulation as set forth in claim 1, wherein said nicotinic acid is in an amount of about 1000 mg.

3. A formulation as set forth in claim 1 or 2, wherein the oral sustained release solid dosage form is an oral sustained release tablet.

4. A formulation as set forth in any one of claims 1 to 3, wherein said single daily dose is effective to elevate HDL cholesterol in the patient.

5. A formulation as set forth in any one of claims 1 to 4, wherein said single daily dose is effective to induce at least some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) in the patient.

6. A formulation as set forth in any one of claims 1 to 5, wherein said single daily dose causes no treatment-limiting increase in uric acid in the patient.

7. A formulation as set forth in any one of claims 1 to 6, wherein said single daily dose treatment causes no treatment-limiting increase in free fasting glucose in the patient.

8. A formulation as set forth in any one of claims 1 to 7, wherein said single daily dose treatment causes no anomalies in a liver function test in the patient to an extent which would require daily treatment to be discontinued, and wherein the liver function test is selected from the group consisting of an AST, ALT
and alkaline phosphatase liver function test.

9. A formulation, as set forth in any one of claims 1 to 8, wherein said oral sustained release formulation is in the form of a tablet which contains:
(a) about 30% to about 90% parts by weight nicotinic acid, and (b) about 5% to about 50% parts by weight hydroxypropyl methylcellulose as said swelling agent.

10. Use of a formulation as set forth in any one of claims 1 to 9 for treating hyperlipidemia in a patient without inducing treatment-limiting (i) hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both to an extent which would require the use of said formulation to be discontinued.