AU2009200874A1 - Nicotinic acid compositions for treating hyperlipidemia and related methods therefor - Google Patents

Description

S&F Ref: 477622D3

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Kos Life Sciences, Inc., of Suite 2502, 1001 Brickell Bay Drive, Miami, Florida, 33131, United States of America Eugenio A Cefali Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Nicotinic acid compositions for treating hyperlipidemia and related methods therefor The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(2002252_1) 6 Nicotinic Acid Compositions for Treating Hyperlipidemia and Related 0 SMethods Therefor 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, o 0 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 0o hyperlipidemia in a once per day oral dosage form given during the evening hours.

Background 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 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 A477622dlspci -2- Hyperlipidemic Subjects: Clues to Mechanism of Action ofNiacin"; Metabolism 34/7, 1985, page 647. The chief advantage of this profile is the ability of nicotinic acid to decrease total Scholesterol, 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 S 5 hyperlipidemics to whom the compound is administered.

00 SIn 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, C1 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.

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

M

(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 -3- Sreduction in triglycerides 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, 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 00 O al (Am J. Med 93: 102 1992). There is also great concern regarding the potential of these Sformulations 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 Hypercholsterolemic 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, 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." 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 ofNiacin", 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, 4 O LDL cholesterol, triglycerides and Lp(a) as well as increases in HDL particles, with an

C

acceptable safety profile, especially as regards liver toxicity and effects on glucose Smetabolism and uric acid levels.

Summary of Invention In brief, the present invention alleviates and overcomes certain of the above- Sidentified problems and shortcomings of the present state of nicotinic acid therapy 00 0 through the discovery of novel nicotinic acid formulations and methods of treatment.

It is therefore, an object of the present invention to provide a composition of C, nicotinic acid or any compound which is metabolized by the body to form nicotinic acid to for treating hyperlipidemia.

It is another object of the present invention to provide a composition as above, which has a time release substance characteristic.

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.

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.

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.

The present invention also provides an orally administered antihyperlipidemia composition which comprises from about 30% to about 90% parts by weight of nicotinic A477622dlspci 0 acid; and, from about 5% to about 50% parts by weight of hydroxypropyl 0 methylcellulose.

SThe 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 Sexcipients to provide sustained release of drug. The method also includes the step of o Sorally 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 o0 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.

A477622dlspec -6o The other compounds specifically include, but are not limited to the following: nicotinyl alcohol Startrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol and d,l-alpha-tocopheryl Snicotinate. 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 t" 5 hyperlipidemia, which condition is characterized by the presence of excess fats such as cholesterol r- 00 0 and triglycerides, in the blood stream. According to the present invention, a sustained release Scomposition 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 milligrams (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 -7the 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 Sa period of time. As is known in the art, such swelling agents and amounts thereof, may be 5 preselected in order to control the time release of the active ingredient. Such swelling agents 00 Sinclude, 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 i 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 ot 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.

-8- 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.

00 General Experimental In order to demonstrate the effectiveness of the compositions and method of the present N, 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 TABLE 1A hereinbelow.

TABLE IA Test Tablet Composition Ingredient 375 m 500 mg 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 -9- O 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 ofhydrophilic polymer used.

1 5 A Niaspan® formulation consists of Niacin, Methocel® E1OM Premium, Povidone oO 00 0and Hystrene 5016 (stearic acid). Methocel® E1OM Premium is utilized as a controlled-release Sagent in the Niaspan® formulation. Methocel is a partly O-methylated and 0-(2hydroxypropylated) 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.

Providone is a synthetic polymer consisting of linear I-vinyl-2-pyrrolidone groups, the degree ofpolymerization 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 Kvalue, 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® 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 E10M and Povidone K90. The granulation process improves compression properties.

10 TABLE TB1 pan® Tablet Formulations f NiaspanOD Product I 375mg Tablets 500mg Tablets f750mg Tablets 11000mg 1 Tablets Formulation- Tablets Niacin 64.4 70.5 77.4 83.1 Methocel ElIOM 7.4 8.1 8.9 Premium (Intragranular) 2.2 2.4 2.7 2.9 Providone Methocel ElIOM 25.0 18.0 10.0 Premium (Extragranular) Hystrene 5016 1.0 1.0 1.0 (Stearic Acid)__ Table weight, mg 582.5 j 709.5 968.6 1203.6 Niaspan® formulations are presented in white caplet shape tablets. Caplet dimensions differ with respect to product strength. The 3 75mg 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 .0.750" x 0.320". Target tablet weight and hardness dictate thickness across the four Niaspan® products. The production of the NiaspanO tablets will now be described generally as set forth below.

SUBSTITUTE SHEET (RULE 26) -1I1 Niaspang Granulation Process Flow Chart Process Flow Granulate Equipment High shear granulator (Littleford FMI Niacin Providone K90 Methocel E IOM (Intragranular) Purfied Water Dry Fluid bed drier (Glatt fluid bed drier)

MNO

(Kemutec Betagrind) Parcel size reduction Niaspan® 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 Pess FIQw- Eqimenti Methocel

MIOM

(Extragranular) H-ystrene 5016 (Stearic acid) NiaspanO Tablet Blend Blend Miled Niaspan® granules with extragranular Methocel El OM and Hystrene 5016 NiaspanO Table Manufacture Compress Niaspan® Tablet Blend Blender (Patterson-Kelley V-Blender) Roarly tablet press Niaspan® Tablet Process Description A Niaspan®& tablet blend is manufactured by blending the Niaspan® granulation, extragranular Methocel EIOM and Hystrene 5016. The quantities of each NiaspanOD tablet blend -12component will depend on the particular Niaspan® dose being manufactured (refer to Table IB).

A Niaspan® tablet blend is compressed to form Niaspan® tablets. Niaspan® tablet physical properties will vary depending on the particular Niaspan® dose being manufactured.

Production ofNiaspan® tablets will now be discussed in greater detail. The initial stage of manufacturing is the same for all four tablet strengths of Niaspan® (375, 500, 750 and 1000mg). One batch of Niaspan® granulation is comprised of four individual 40.0kg units of 00 granulation which are processed separately, but under like conditions. The four individual Sgranulations are sampled and tested individually and subsequently released for blending. The base 0granulation is not strength specific and may be used to manufacture any tablet strength of O 10 Niaspan®.

The ingredients in the base granulation are set froth in Table IC below: TABLE IC Component Function Quantity per per Quantity per kilogram kilogram 160.00 kg granulation (kg) granulation batch (kg) Niacin, USP Drug Substance 0.87 87.00 139.20 Povidine, UPS Binder 0.03 3.00 4.80 Methocel USP, Controlled- 0.10 10.00 16.00 E 1OM Premium Release Agent CR Grade Purified Water, Granulation 0.00* 0.00' 48 USP* Reagent 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 polyethylenelined 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 E1OM 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 1-minute pre-mix cycle, about 12.0i0.05kg SUBSTITUTE SHEET (RULE 26) -13of Purified Water, USP are sprayed onto the powder bed at a rate of about 2.40±0.24kg/minute.

Immediately following the addition of the Purified Water, USP, the unit is granulated for about minutes.

i 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 r- 0o 70C±5"C. The unit is dried until a moisture level of is obtained as determined using a 0 Computrac® Moisture Analyzer, model MASA. The dried granulation is discharged into S appropriately labeled, double polyethylene-lined drums and reconciled.

O 10 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 ft 3 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 EIOM 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 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 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.

-14- TABLE II Patient Study Lipid Profile Data

O

0 (N 0\ Pt. No.

GROUP A 1 2 3 4 5 6 7 8 9 11 Mean p-Value GROUP B 1 2 3 4 6 7 8 9 11 12 -8.2 -5.9 -15.1 -3.3 -16.5 -12.4 -24.2 -6.7 4.5 2.8 -13.0 -8.9 0.0004-8.9 -12.0 -27.0 -13.0 -10.0 -17.7 -25.9 -31.4 -7.4 1.1 -0.2 -9.4 -13.9 0.0001- 13.9 -27.1 -35.7 -33.6 -24.6 -2.1 -32.6 34.0 12.0 -7.7 -18.8 -30.8

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

Total-C LDL-C Trips -17.3 -28.7 -22.0 61.6 -28.8 -42.0 -39.4 -42.4 7.2 -2.7 -54.0 -18.9 0.0371 HDL-C HDL.-C, Rea 22.0 65.0 -9.1 3.8 11.1 51.6 12.5 18.8 9.2 22.9 44.3 23.0 0.0068

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

-19.2 -32.2 -21.4 -19.9 -3.3 23.1 24.8 10.1 -2.9 -10.5 -20.0 -24.4 -28.0 -35.6 -15.1 -29.4

PATIENT

-42.6 -28.4 -16.8 -28.0 -25.3 -30.4 -33.4 20.0 -60.4 4.3 -33.4 30.4 -20.8 9.6 -41.1 5.8 WITHDREW FROM STUDY -58.6 49.2 5.5 6.5 -11.6 20.7 -59.0 53.1 -53.4 31.8 11.7 21.1 22.3 3.2 38.6 16.1 2.4 68.9 -6.8 -12.3 70.5 39.7 25.0 -81.9 -25.3 -17.4 -27.0 -22.4 -14.3

NA

40.6 -41.2

NA

-28.4 17.4 16.8 -17.5 -17.5 51.3 51.9 38.5 TABLE II (Continued) SPatient Study Lipid Profile Data SPt. No. Total-C LDL-C AoB Igs HL-C HL= a 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 Sp-Value 0.0002 <0.0001 0.0001 <0.001 <0.0001 0.0002 <0.0188 00 Combined -8.7 -13.3 Gp B -26.1 25.3 GpB Gp B p-Value 0.0002 <0.0001 only <.0001 <0.0001 only only 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 triglyceride 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 oncea-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 IIl-VII hereinbelow.

16 TABLE Ill THE EFFECT OF NIASPAN® THERAPY ON AST (SGOT) LEVELS (U[L) (1500 mngs dosed once-a-day at night) (n 28) Weeks of Therapy With NiaspanO Baseline 00 GROUP A 0 1 2 3 4 6 7 8 9 11 GROUP B 1 2 3 4 6 P 7 8 9 11 12 13 2 Wks.

29 25 18 16

NA

17 17 21 16 21 21 4 Wks.

25 24 22 15 32 17 14 22 17 21 22 Reference Range 23 20 20 15 20 25 22 23 21 ATIENT WITHDREW DUE TO FLUSING 21 18 18 19 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 050 0-s0 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 TABLE Ml (Continued) THE EFFECT OF NIASPAN® THERAPY ON AST (SGOT) LEVELS (U/L) (1500 rugs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan® t#Baseline 2 k.4 Wks. 8 Wks. Reference 00 Range 14 18 25 20 18 0-50 Combined Mean 19.8 20.4 20.8 21.1 Change From +6.6% Baseline Level of Significance: 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, W.Wi Reference R~ange 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 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 14 15 17 19 0-55 11 18 18 20 16 0-55 18- TABLE IV (Continued) THE EFFECT OF NIASPAN® THERAPY ON ALT (SGPT) LEVELS (UJL) (1500 mgs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan® t#Baseline GROUP B 1 16 2 16 3 13 4 23 21 6 PATIENT WITHDREW] 7 21 8 18 9 11 8 11 17 12 14 13 14 14 23 Combined 17.7 Mean Change From Baseline Level of Significance: p=0.3 424 2 Wks.

17 14 Reference Rage 20 26 23 17 DUE TO FLUSHING 16 18 20 5 10 12 18

NA

23 17.5 1% 17 11 14 18 20 11 19 19.3 9.0% 29 22 16 17 15 21 18 8 17 16 16 10 19 18.2 0-55 0-55 0-55 055 0-55 0-55 0-55 0-55 0-55 0-55 0-55 0-55 0-55 +2.8%

I

-19- TABLE V THE EFFECT OF NIASPAN® THERAPY ON ALKALINE PHOSPHATASE LEVELS (UIL) (1500 mgs dosed once-a-day at night) (ni 28) Weeks of Therapy With Niaspan®g 00 GROUP A 2 3 4 5 6 7 8 9 10 I1I GROUP B 1 Baseline 56 100 45 68

NA

48 71 49 55 73 18 4 Wks 57 89 53 71 74 49 79 47 56 75 20 55 102 51 91 81 51 75 50 45 75 16 95 71 82 38 61 58 73 93 Reference Range 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 20-140 2 3 4 6 7 8 9

PA

73 67 89 82 64 72 73 69 72 37 36 37 65 53 54 TIENT WITHDREW DUE TO FLUSHING TABLE V (Continued) THE EFFECT OF NIASPAN® THERAPY ON ALKALINE PHOSPHATASE LEVELS (UAL) (1500 mngs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan& w~t Baseline Reference Range 13 14 Combined Mean Change From Baseline 59 64 72 66.5 67 67 59 68 61 61.5 -6.1% 70 63 59 66 59 63.3 -3.4% 20-140 20-140 20-140 20-140 20-140 65.8 +0.005% Level of Significance: p=0.0 2 36 -21- 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® 00 Baseline GROUP A

I

2 3 4 5 6 7 8 9 10 I1I GROUP B 1 2 3 4 6 PA 7 8 9 5.2 4.0 6.3 3.1 3.4 6.6 3.8 4.4 3.9 2.6 4.7 5.0 4.6 7.0 4.6

NA

5.5 4.5 3.8 4.5 2.9 5.5 4 Wks, 4.8 4.5 6.5 4.2 3.3 5.6 4.3 5.1 4.6 2.8 5.2 4.7 3.6 5.5 5.1 4.1

FLUS~I-NG

6.6 5.4 5.1 4.3 6.2 6.2 3.8 4.2 4.7 4.9 4.5 3.5 2.7 5.3 3.5 2.3 5.3 3.6 3.8 6.8 5.6 3.8 Reference Range 4.0-8.5 2.5-7.5 4.0-8.5 2.5-7.5 2.5-7.5 4.0-8.5 2.5-7.5 2.5-7.5 2.5-7.5 2.5-7.5 2.5-7.5 2.5-7.5 4.0-8.5 2.5-7.5 4.0-8.5 2.5-7.5 2.5-7.5 2.5-7.5 2.5-7.5 3.7 4.2 2.8 3.5 4.2 5.3 4.7 3.9 3.7 4.1 TIENT WITHDREW DUE TO 5.8 6.6 22 TABLE VI (Continued) THE EFFECT OF NIASPAN® THERAPY ON URIC ACID LEVELS (mgldL) (1500 mngs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan® t#Baseline 2..Wksi 4MWks. 8 ks Reference 5.6 4.2 5.5 4.54 5.4 4.6 5.4 4.82 +6.2% 4.4 2.8 6.2 4.6 6.1 4.92 +8.4% 8.5 5.0 5.6 5.3 5.3 4.86 2.5-7.5 2.5-7.5 4.0-8.5 2.5-7.5 2,5-7.5 *p= 0 3450 14 Combined Mean Change From Baseline *Level of Significance: p=.3 4 -23 TABLE VII THE EFFECT OF NIASPAN® THERAPY ON FASTING GLUCOSE LEVELS (mg/dL) (ni 28) Weeks of Therapy With Niaspan® Baseline 00 ALtr GROUP A 1 2 3 4 6 7 8 9 11 GROUP B 1 2 3 4 6 PA 7 8 9 114 101 99 100 89 97 85 98 97 94 102 2 Wks 122 105 98 118

NA

103 107 107 97 101 103 4 Wks.

123 107 109 94 82 94 100 103 100

III

95 110 101 103 94 103 107 94 101 110 97 95 99 89 97 125 95 117 108 92 105 Reference Range 70-115 80-125 70-115 80-125 80-125 70-115 80-125 80-125 80-125 70-115 80-125 70-115 80-125 70-115 80-125 70-115 70-115 70-115 70-115 70-115 101 97 83 90 95 96 96 98 95 116 139 113 88 98 91 TIENT WMTHDREW DUE TO FLUSHiNG 106 114 118 106 84 122 -24- TABLE VII (Continued) THE EFFECT OF NIASPAN® THERAPY ON FASTING GLUCOSE LEVELS (mg/dL) (n 28) Weeks of Therapy With Niaspan® 11 85 12 92 13 99 14 100 Combined 98.4 Mean Change From Baseline Level of Significance: p=0.0 0 2 1 2Wks 106 89 105 108 105.8 +7.5% 106 101 94 84 101.6 +3.3% 108 86 100 107 102.3 Reference Range 70-115 80-125 70-125 70-125 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.

2009200874 05 Mar 2009 TABLE VI A Comparison of Changes in Liver Function Tests

DOSE

0500 J 1000 1500 f 2000 2500 McKenney Srb AST F 23.8 27.9 40.4 36.6 56.5 na 117 170 j 154 237 na Invention Dosage AST 24.3 r na f 23.7 17.5 26.6 1146 na 98 f 113 109 ALT 25.6 F 29.5 36.3 39.0 59.1

NA

f 115 142 152 231

NA

Invention Dosage I ALT F 21.4 r na 18.7 22.6 21.3 j 22.4 na 87 106 100 F 05 McKenney SR Niacin ALK 9595 106 15136 na.

3000 TOTAL I

I

97.0 408 [27.8 1114 1100.0r 121.8 1102I 2009200874 05 Mar 2009 TABLE VIII (Continued) A Comparison of Changes in Liver Function Tests r r 0 500 1000 100 Invention Dosage

ALK

74.7 na na 112 73.9 99 I SOC 76.1 1-I02

DOSE

2000 2500 13000 ITOTAL~ 143 [142 1_ 73.4 76.7 [78.0*1 f 98 ~~103 r McKenney SR Niacin Drop t 0 i-- F 0 1 2 2 9 9 30 0 [0 0 26 670 97 0 01~ 0 invention Dosage Drop n7 year [1 na na.

[0 35 10 31 F-89- 7 30 100 18 23 I--1 78 [240 101 j77 _1 year I -27- Dosed twice-per-day as described in "A Comparison of the Efficacy and Toxic Effects of N Sustained vs Immediate Release Niacin in Hypercholesterolemic Patients" by McKenney et al..

Journal of the American Medical Association, March 2, 1994; Vol. 271, No. 9, pages 672-677.

b SR is "sustained release" c Dosed once-per-day at night The results of the comparison of the studies reported in Table VIII show that the control 4 group (the McKenney group) had 18 of 23, or 78 percent of the patients therein drop out of the o0 test because of an increase in their respective liver function tests. The patients withdrew at the 0 0 direction of the investigator. In comparison, a group of 240 patients treated according to the 0 present invention had zero patients drop out, based upon the same criteria for withdrawal. The Stest results reported above indicate that this sustained release dosage form caused no elevation in liver function tests no liver damage), no elevations in uric acid and only a small, 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 ofLDL 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 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 may fall within the scope of the attached claims.

Claims (84)

1. A daily method of treating hyperlipidemia in a patient without inducing treatment-limiting liver damage, said daily method comprising orally dosing the patient t with an effective antihyperlipidemic amount of nicotinic acid once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least Sone pharmaceutically acceptable carrier 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 dose treatment causing little or no serious damage to the liver of the patient. 00

2. Nicotinic acid combined with at least one pharmaceutically acceptable carrier Sto form an oral sustained release solid dosage form, which does not contain an internal hydrophobic component, and wherein a single daily dose of said sustained release solid Sdosage form causes little or no serious damage to the liver, when used in treating hyperlipidemia.

3. Nicotinic acid combined with at least one pharmaceutically acceptable carrier to form an oral sustained release solid dosage form, which does not contain an internal hydrophobic component, and wherein a single daily dose of said sustained release solid dosage form causes little or no serious damage to the liver, for use in treating hyperlipidemia.

4. Use of nicotinic acid combined with at least one pharmaceutically acceptable carrier to form an oral sustained release solid dosage form, which does not contain an internal hydrophobic component, and wherein a single daily dose of said sustained release solid dosage form causes little or no serious damage to the liver, in the manufacture of a medicament for treating hyperlipidemia.

5. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein the patient is dosed with from about 250mg to about 3000mg of nicotinic acid.

6. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein the oral sustained release solid dosage form is an oral sustained release tablet.

7. A method, dosage form or use as set forth in claim 6, wherein the oral sustained release solid dosage form contains nicotinic acid in an amount selected from the group consisting of about 375mg, about 500mg and about 750mg.

8. A method, dosage form or use as set forth in any one of claims I to 4, wherein said single daily dose treatment elevates HDL cholesterol in the patient.

9. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein said single daily dose treatment induces at least some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) in the patient. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein said single daily dose treatment causes little or no serious increase in uric acid in the patient.

11. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein said single daily dose treatment causes little or no serious increase in free fasting glucose in the patient. A477622dispca

12. A method, dosage form or use as set forth in any one of claims 1 to 4, wherein Ssaid single daily dose treatment causes little or no serious increase in a liver function test C in the patient, and wherein the liver function test is selected from the group consisting of t an AST, ALT and alkaline phosphatase liver function test. s 13. A composition for treating hyperlipidemia in a patient with an effective Samount of nicotinic acid once per day during the evening or at night, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable component to form an oral sustained release solid dosage form, and wherein said oral sustained release solid dosage form does not contain an internal hydrophobic component.

14. A composition, as set forth in claim 13, wherein said oral sustained release O solid dosage form comprises from about 250mg to about 3000mg of nicotinic acid. A composition, as set forth in claim 13, wherein said oral sustained release 0solid dosage form is an oral sustained release tablet. c

16. A composition, as set forth in claim 14, wherein said oral sustained released tablet contains nicotinic acid in an amount selected from the group consisting of about 375mg, about 500mg and about 750mg.

17. A composition, as set forth in claim 13, wherein said oral sustained release tablet contains about 375mg nicotinic acid, about 189mg hydroxypropyl methylcellulose as a swelling agent, about 13mg polyvinyl pyrrolidone as a binder, and about 6mg of stearic acid as a lubricant.

18. A composition, as set forth in claim 13, wherein said oral sustained release tablet contains about 500mg nicotinic acid, about 203mg hydroxypropyl methylcellulose as a swelling agent, about 17mg polyvinyl pyrrolidone as a binder, and about 7mg stearic acid as a lubricant.

19. A composition, as set forth in claim 13, wherein said oral sustained release tablet contains about 750mg nicotinic acid, about 205mg hydroxypropyl methylcellulose as a swelling agent, about 26mg polyvinyl pyrrolidone as a binder, and about 10mg stearic acid as a lubricant. A composition, as set forth in claim 13, wherein said oral sustained release tablet contains about 30% to about 90% by weight nicotinic acid, about 5% to about 50% by weight hydroxypropyl methylcellulose as a swelling agent, about 1% to about 5% by weight polyvinyl pyrrolidone as a binder, and about 0.5% to about 2% by weight stearic acid as a lubricant.

21. A composition, as set forth in claim 13, wherein said oral sustained release tablet contains about 30% to about 90% by weight nicotinic acid, and about 5% to about 50% by weight hydroxypropyl methylcellulose as a swelling agent.

22. A method of treating hyperlipidemia in a patient without inducing treatment- limiting hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both, said method comprising orally dosing the patient with an effective antihyperlipidemic amount of nicotinic acid once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable component to form an oral sustained release solid dosage form, and wherein A477622dlspeci \the oral sustained release solid dosage form does not contain an internal hydrophobic 0 component, and wherein the oral sustained release solid dosage form is effective in reducing a serum lipid without causing treatment-limiting hepatotoxicity and (ii) t elevations in uric acid levels or glucose levels or both in the patient to a level which would require said treatment to be discontinued by the patient when it is ingested by the Spatient once per day during the evening or at night as the single dose in accordance with said single dose treatment.

23. Nicotinic acid administered once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least one pharmaceutically 00 10 acceptable component to form an oral sustained release solid dosage form, and wherein Sthe oral sustained release solid dosage form does not contain an internal hydrophobic component, and wherein the oral sustained release solid dosage form is effective in Sreducing a serum lipid without causing treatment-limiting hepatotoxicity and (ii) elevations in uric acid levels or glucose levels or both, when used in treating hyperlipidemia.

24. Nicotinic acid administered once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable component 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, and wherein the oral sustained release solid dosage form is effective in reducing a serum lipid without causing treatment-limiting hepatotoxicity and (ii) elevations in uric acid levels or glucose levels or both, for use in treating hyperlipidemia. Use of nicotinic acid administered once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable component 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, and wherein the oral sustained release solid dosage form is effective in reducing a serum lipid without causing treatment-limiting (i) hepatotoxicity and (ii) elevations in uric acid levels or glucose levels or both, in the manufacture of a medicament for treating hyperlipidemia.

26. A composition of nicotinic acid for oral administration to a patient once per day during the evening or at night as the patient lies down to go to sleep for providing an effective antihyperlipidemic amount of nicotinic acid to the patient during times of peak lipid production or synthesis by the patient to induce 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, without causing abnormalities in uric acid levels or glucose levels or both to an extent which would require said daily treatment to be discontinued by the patient, the sustained release composition comprising an effective antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release of the nicotinic acid, and wherein the sustained release solid dosage form does not contain an internal hydrophobic component. A477622dIspeci

27. A daily method of treating hyperlipidemia in a patient comprising orally Sadministering to the patient a sustained release composition of nicotinic acid once per day C during the evening for providing an effective antihyperlipidemic amount of nicotinic acid Sto the patient without causing abnormalities in uric acid levels or glucose levels or both to an extent which would require said daily treatment to be discontinued by the patient, the Ssustained release composition comprising an effective antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release of the nicotinic acid.

28. A sustained release composition of nicotinic acid comprising an effective antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release S0to of the nicotinic acid, when used in treating hyperlipidemia daily. S29. A sustained release composition of nicotinic acid comprising an effective \antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release Sof the nicotinic acid, for use in treating hyperlipidemia daily. C

30. Use of a sustained release composition of nicotinic acid comprising an effective antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release of the nicotinic acid, in the manufacture of a medicament for treating hyperlipidemia daily.

31. A method, composition or use as set forth in any one of claims 27 to wherein the patient is dosed with from about 250mg to about 3000mg of nicotinic acid.

32. A method, composition or use as set forth in any one of claims 27 to wherein said single dose treatment induces at least some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) in the patient.

33. A method, composition or use as set forth in any one of claims 27 to wherein said single dose treatment elevates HDL cholesterol in the patient.

34. A sustained release composition of nicotinic acid for oral administration to a patient once per day during the evening or at night for providing an effective antihyperlipidemic amount of nicotinic acid to the patient to induce 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, without causing abnormalities in uric acid levels or glucose levels or both to an extent which would require the use of said sustained release composition by the patient to be discontinued, said sustained release composition comprising an effective antihyperlipidemic amount of nicotinic acid, and (ii) an excipient to provide sustained release of the nicotinic acid. A sustained release composition of claim 34, wherein the excipient is selected from the group consisting of a swelling agent, a binder, a processing aid and mixtures thereof

36. A sustained release composition of claim 35, wherein the swelling agent is selected from group consisting of a polymer, a wax, a natural material and mixtures thereof.

37. A sustained release composition of claim 36, wherein the polymer is selected from the group consisting of hydroxypropyl methylcellulose, sodium carboxymethylcellulose and ethylcellulose. A477622dlspeci

38. A sustained release composition of claim 36, wherein the wax is bees wax.

39. A sustained release composition of claim 36, wherein the natural material is selected from the group consisting of gums and gelatins. S 40. A sustained release composition of claim 35, wherein the binder is povidone. C 41. A sustained release composition of claim 35, wherein the processing aid is a t lubricant.

42. A sustained release composition of claim 41, wherein the lubricant is stearic acid.

43. A sustained release composition of claim 37, wherein the hydroxypropyl 0 to methylcellulose is in an amount ranging from about 5 to about 50 parts by weight per 100 Sparts by weight of the sustained release composition.

44. A sustained release composition of claim 35, wherein the binder is in an Samount ranging from about 1 to about 5 parts by weight per 100 parts by weight of the c sustained release composition.

45. A sustained release composition of claim 35, wherein the processing aid is in an amount ranging from about 0.5 to about 2 parts by weight per 100 parts by weight of the sustained release composition.

46. A sustained release composition of claim 34, wherein the sustained release composition consists essentially of nicotinic acid, hydroxypropyl methylcellulose, povidone and stearic acid.

47. A sustained release composition of claim 34, wherein the sustained release composition consists essentially of nicotinic acid 375.0mg, hydroxypropyl methylcellulose 188.75mg, povidone 2.9mg, and stearic acid 5.8mg.

48. A sustained release composition of claim 34, wherein the sustained release composition consists essentially of nicotinic acid 500.0mg, hydroxypropyl methylcellulose 203.0mg, povidone 17.2mg, and stearic acid 7.3mg.

49. A sustained release composition of claim 34, wherein the sustained release composition consists essentially of nicotinic acid 750.0mg, hydroxypropyl methylcellulose 204.7mg, povidone 25.9mg, and stearic acid 9.9mg.

50. A daily method of treating hyperlipidemia in a patient without inducing treatment-limiting elevations in uric acid levels or glucose levels or both in the patient, said daily method comprising orally dosing the patient with an effective antihyperlipidemic amount of nicotinic acid once per day during the evening or at night as a single dose, wherein said single dose treatment induces at least some decrease in s3 levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and (ii) some elevation in HDL cholesterol in the patient, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable carrier to form an oral sustained release solid dosage form.

51. A single dose of nicotinic acid wherein said single dose treatment induces at least some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and (ii) some elevation in HDL cholesterol, when used in treating hyperlipidemia A477622dispci daily without inducing treatment-limiting elevations in uric acid levels or glucose levels Sor both. C

52. A single dose of nicotinic acid wherein said single dose treatment induces at t least some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and (ii) some elevation in HDL cholesterol, for use in treating hyperlipidemia daily Swithout inducing treatment-limiting elevations in uric acid levels or glucose levels or both.

53. Use of a single dose of nicotinic acid wherein said single dose treatment r induces at least some decrease in levels of total cholesterol, LDL cholesterol, 00 0to triglycerides and Lp(a) and (ii) some elevation in HDL cholesterol, in the manufacture of a medicament for treating hyperlipidemia daily without inducing treatment-limiting elevations in uric acid levels or glucose levels or both.

054. A method, single dose of nicotinic acid or use as set forth in any one of claims c 50 to 53, wherein the patient is dosed with from about 250mg to about 3000mg of nicotinic acid A method, single dose of nicotinic acid or use as set forth in any one of claims to 53, wherein the oral sustained release solid dosage form is an oral sustained release tablet.

56. A method, single dose of nicotinic acid or use as set forth in claim wherein the oral sustained release tablet contains nicotinic acid in an amount selected from the group consisting of about 375mg, about 500mg and about 750mg.

57. A method of treating hyperlipidemia in a patient without inducing treatment- limiting hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both, said method comprising orally dosing the patient with an effective antihyperlipidemic amount of nicotinic acid once per day during the evening or at night as a single dose, wherein the nicotinic acid is combined with at least one pharmaceutically acceptable component to form an oral sustained release solid dosage form, wherein the oral sustained release solid dosage form is effective in reducing a serum lipid without causing treatment-limiting hepatotoxicity and elevations in uric acid levels or glucose levels or both in the patient to a level which would require said treatment to be discontinued by the patient when it is ingested by the patient once per day during the evening or at night as the single dose in accordance with said single dose treatment.

58. An oral sustained release solid dosage form of nicotinic acid effective in reducing a serum lipid without causing treatment-limiting hepatotoxicity and (b) elevations in uric acid levels or glucose levels or both, when used in treating hyperlipidemia without inducing treatment-limiting hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both.

59. An oral sustained release solid dosage form of nicotinic acid effective in reducing a serum lipid without causing treatment-limiting hepatotoxicity and (b) elevations in uric acid levels or glucose levels or both, for use in treating hyperlipidemia without inducing treatment-limiting hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both. A477622dIspcd Use of an oral sustained release solid dosage form of nicotinic acid effective 0 in reducing a serum lipid without causing treatment-limiting hepatotoxicity and (b) c elevations in uric acid levels or glucose levels or both, in the manufacture of a ic medicament for treating hyperlipidemia without inducing treatment-limiting (i) s hepatotoxicity and (ii) abnormalities in uric acid levels or glucose levels or both. t 61. A daily method of treating hyperlipidemia in a patient comprising orally administering to the patient a sustained release composition of nicotinic acid once per day during the evening or night for providing an effective antihyperlipidemic amount of nicotinic acid to the patient during times of peak lipid production or synthesis by the 0to patient to induce at least some lowering of total cholesterol, LDL cholesterol, triglycerides and Lp(a) and at least some increase in HDL cholesterol in the patients blood stream, without causing abnormalities in liver function tests and uric acid levels or glucose levels to an extent which would require said daily treatment to be discontinued by c the patient, the sustained release composition comprising an effective antihyperlipidemic amount of nicotinic acid and an excipient to provide sustained release of the nicotinic acid.

62. A sustained release composition of nicotinic acid, when used in treating hyperlipidemia daily for providing an effective antihyperlipidemic amount of nicotinic acid to a patient during times of peak lipid production or synthesis by the patient to induce 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, without causing abnormalities in liver function tests and uric acid levels or glucose levels.

63. A sustained release composition of nicotinic acid, for use in treating hyperlipidemia daily for providing an effective antihyperlipidemic amount of nicotinic acid to a patient during times of peak lipid production or synthesis by the patient to induce 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, without causing abnormalities in liver function tests and uric acid levels or glucose levels.

64. Use of a sustained release composition of nicotinic acid, in the manufacture of a medicament for treating hyperlipidemia daily for providing an effective antihyperlipidemic amount of nicotinic acid to a patient during times of peak lipid production or synthesis by the patient to induce 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, without causing abnormalities in liver function tests and uric acid levels or glucose levels. A sustained release composition of nicotinic acid for oral administration to a patient once per day during the evening or night or as the patient lies down to go to sleep for providing an effective antihyperlipidemic amount of nicotinic acid to the patient during times of peak lipid production or synthesis by the patient to induce 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, without causing abnormalities in liver function tests and uric acid levels or glucose levels or both to an extent which A477622dispcci \would require the use of said sustained release composition by the patient to be Sdiscontinued, the sustained release composition comprising an effective c antihyperlipidemic amount of nicotinic acid, and (ii) an excipient to provide sustained t release of the nicotinic acid. s 66. A method of treating hyperlipidemia in a hyperlipidemic comprising dosing Sthe hyperlipidemic once per day during the evening or at night with an effective antihyperlipidemic amount of a compound which is metabolised to nicotinic acid by the hyperlipidemic to produce a reduction in total and LDL cholesterol, triglycerides and Lp(a), and (ii) an increase in HDL cholesterol, wherein the compound is combined with at 0 10o least one pharmaceutically acceptable carrier to form an oral solid dosage form, and Swherein the compound is selected from the group consisting of d-glucitol hexanicotinate, \aluminium nicotinate and 1-alphaoctopheryl nicotinate.

67. A compound selected from the group consisting of d-glucitol hexanicotinate, c aluminium nicotinate and 1-alphatocopheryl nicotinate which is metabolised to nicotinic acid, when used in treating hyperlipidemia.

68. A compound selected from the group consisting of d-glucitol hexanicotinate, aluminium nicotinate and 1-alphatocopheryl nicotinate which is metabolised to nicotinic acid, for use in treating hyperlipidemia.

69. Use of a compound selected from the group consisting of d-glucitol hexanicotinate, aluminium nicotinate and 1-alphayocopheryl nicotinate which is metabolised to nicotinic acid, in the manufacture of a medicament for treating hyperlipidemia. A method of manufacturing a base granulation for producing a sustained release nicotinic acid solid dosage form, said method comprising: forming a wet granulation which consists essentially of nicotinic acid, a controlled-release agent and a granulating/binding agent; drying the wet granulation to form dry granules; milling the dry granules to obtain a substantially uniform particle size distribution; dry blending the dry granules, a controlled-release agent and a processing aid to form a final dosage blend; and forming the sustained release nicotinic acid solid dosage form from the final dosage blend.

71. A method, as set forth in claim 70, said method including the further step of forming a dry mix which consists essentially of nicotinic acid, a controlled-release agent and a granulating: binding agent; and forming the wet granulation from the dry mix.

72. A method, as set forth in claim 70, wherein the sustained release nicotinic acid solid dosage form is a sustained release nicotinic acid tablet.

73. A method, as set forth in claim 70, wherein said oral sustained release solid dosage form comprises from about 250mg to about 3000mg of nicotinic acid.

74. A method, as set forth in claim 72, wherein said oral sustained released tablet contains nicotinic acid in an amount selected from the group consisting of about 375mg, about 500mg and about 750mg. A477622dlispc A method, as set forth in claim 70, wherein the controlled-release agent is Sselected from group consisting of a polymer, a wax, a natural material and mixtures N thereof c76. A method, as set forth in claim 75, wherein the polymer is selected from the s group consisting of hydroxypropyl methylcellulose, sodium carboxymethylcellulose and Sethylcellulose.

77. A method, as set forth in claim 75, wherein the wax is bees wax.

78. A method, as set forth in claim 75, wherein the natural material is selected from the group consisting of gums and gelatins. 00 Sto 79. A method, as set forth in claim 70, wherein the granulating/binding agent is povidone. A method, as set forth in claim 70, wherein the processing aid is a lubricant.

81. A method, as set forth in claim 80, wherein the lubricant is stearic acid

82. A method, as set forth in claim 70, wherein the controlled-release agent is is hydroxypropyl methylcellulose which is in an amount ranging from about 5% to about parts by weight per 100 parts by weight of the sustained release composition.

83. A method, as set forth in claim 70, wherein the binder is in an amount ranging from about 1 to about 5 parts by weight per 100 parts by weight of the sustained release nicotinic acid solid dosage.

84. A method, as set forth in claim 70, wherein the processing aid is in an amount ranging from about 0.5 to about 2 parts by weight per 100 parts by weight of the sustained release nicotinic acid solid dosage. A method, as set forth in claim 70, wherein the sustained release nicotinic acid solid dosage consists essentially of nicotinic acid, hydroxypropyl methylcellulose, povidone and stearic acid.

86. A method of treating hyperlipidemia in a hyperlipidemic comprising dosing the hyperlipidemic with an effective antihyperlipidemic amount of nicotinic acid or a compound that can be metabolized to nicotinic acid by the body, once per day in the evening or at night combined with pharmaceutically acceptable carriers, to provide a reduction in total and LDL cholesterol, triglycerides and Lp(a), with a significant increase in HDL cholesterol.

87. A method, as set forth in claim 86 wherein the hyperlipidemic is dosed with from about 250mg to about 3000mg of nicotinic acid or compound metabolized by the body to nicotinic acid.

88. A method, as set forth in claim 86 which causes little or no serious liver damage, uric acid increases or elevations in fasting glucose levels.

89. A method, as set forth in claim 86 wherein the release rate of nicotinic acid or compound metabolized by the body to nicotinic acid is from about 2.0% per hour to about per hour.

90. A method, as set forth in claim 86, wherein the nicotinic acid or compound metabolized by the body to nicotinic acid is prepared by formulating the active compound A477622dlspcci I \with from about 5 to about 50 parts by weight of hydroxypropyl methylcellulose per 100 O Sparts by weight of tablet.

91. A method, as set forth in claim 86 wherein the nicotinic acid or compound metabolized by the body to nicotinic acid is dosed in the form of a sustained release formulation or tablet containing from about 1 to about 4 parts by weight of binder per 100 Sparts by weight of tablet.

92. A method, as set forth in claim 91 wherein said binder is a polymer having the repeating polymerization unit 1 -ethenyl-pyrrolidone.

93. A method, as set forth in claim 86 wherein the nicotinic acid or compound o00 Sio metabolized by the body to nicotinic acid is dosed in the form of a sustained release formulation or tablet containing from about 0.5 to about 2.5 parts by weight of a lubricating agent per 100 parts by weight of tablet.

94. A method, as set forth in claim 93 wherein the lubricating agent is selected from the group consisting of stearic acid and magnesium stearate.

95. A method, as set forth in claim 86 wherein the compound metabolized by the body to nicotinic acid is nicotinyl alcohol tartrate.

96. A method, as set forth in claim 86 wherein the amount of is from about 100mg to about 500mg per dosage unit.

97. A method, as set forth in claim 86 wherein the compound metabolized by the body to nicotinic acid is selected from the group consisting of d-glucitol hexanicotinate, aluminium nicotinate and 1-alphatocopheryl nicotinate.

98. A composition for treating hyperlipidemia in a patient in need thereof comprising an effective antihyperlipidemic amount of nicotinic acid or a compound metabolized by the body to nicotinic acid and at least one pharmaceutically acceptable excipient, said composition being for administration once daily and wherein administration of said composition once daily to said patient causes little or no treatment- limiting elevations in liver enzymes, little or no abnormalities in glucose or uric acid, induces at least some increase in HDL, and provides some decrease in levels of total cholesterol, LDL cholesterol, triglycerides and Lp(a) in said patient.

99. The composition of claim 98 wherein said compound that can be metabolized to nicotinic acid is selected from the group consisting of D-glucitol hexanicotinate, aluminium nicotinate, D,1-alphatocopherylnicotinate.

100. The composition of claim 98 or claim 99 wherein said at least one pharmaceutically acceptable excipient is selected from the group consisting of a swelling agent, a binder, a processing aid or any mixture thereof.

101. The composition of any one of claims 8 to 10 which comprises about to about 90% by weight nicotinic acid or a compound that can be metabolized to nicotinic acid, about 5% to about 50% by weight of a swelling agent, about 1% to about by weight of a binder, and about 0.5% to about 2% by weight of a lubricant.

102. The composition of any one of claims 98 to 101 wherein said effective antihyperlipidemic amount of nicotinic acid or a compound that can be metabolized to nicotinic acid is from about 250mg to about 3000mg of nicotinic acid. A477622dispec I

103. The composition of any one of claims 100 to 101 which contains nicotinic Sacid or a compound that can be metabolized to nicotinic acid in an amount selected from c the group consisting of about 375mg, about 500mg, about 750mg and about 1000mg. S104. The composition of any one of claims 8 to 13 which is a solid oral dosage form. n

105. The composition of claim 104 which is an oral sustained-release composition. Dated 3 March, 2009 Kos Life Sciences, Inc. 00 S1o Patent Attorneys for the Applicant/Nominated Person c SPRUSON FERGUSON CA A477622dlspci