AU775967B2 - Starter kit containing nicotinic acid compositions - Google Patents

Description

S&F Ref: 477610D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: L-6 Soeces Kos Pharmaceuticak, Inc.

Suite 2502 1001 St ys. re Drive Miami Florida 33131 United States of America 4 alJ d 801 SFC Eugnimo A. Cofar 7 OF Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Starter Kit Containing Nicotinic Acid Compositions The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c STARTER KIT CONTAINING NICOTINIC ACID COMPOSITIONS Related Patent Applications This application for U.S. patent is a Title 35, §11 l(a) application which is a continuation of U.S. Patent Application, Serial No. 08/368,378 filed January 14, 1995, which is a continuation-in-part of U.S. Patent Application, Serial No. 08/124,392, filed September 1993.

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.

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 Hyperlipidemic Subjects: Clues to Mechanism of Action of Niacin"; Metabolism 34/7, 1985, page -2- 647. The chief advantage of this profile is the ability of nicotinic acid to decrease total cholesterol, LDL cholesterol, triglycerides and Lp(a) while increasing HDL particles. While such a regimen does produce beneficial effects, cutaneous flushing and the like still often occurs in the hyperlipidemics to whom the compound is administered.

In order to avoid or reduce the cutaneous flushing, a number of materials have been suggested for administration with an effective antihyperlipidemic amount of nicotinic acid, including guar gum in U.S. Pat. No. 4,965,252, and mineral salts, as disclosed in U.S. Pat. No.

5,023,245; or inorganic magnesium salts as reported in U.S. Pat. No. 4,911,917. These materials have been reported to avoid or reduce the cutaneous flushing side effect commonly associated with nicotinic acid treatment.

Another method of avoiding or reducing the side effects associated with immediate release niacin is the use of sustained release formulations. Sustained release formulations are designed to slowly release the compound from the tablet or capsule. The slow drug release reduces and prolongs blood levels of drug and thus minimizes the side effects. Sustained release formulations of niacin have been developed, such as Nicobid TM capsules (Rhone-Poulenc Rorer), Endur-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 for the sustained release versus -38% for the immediate release) -3and lower increase in HDL cholesterol, represented at HDL 2 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 ct 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 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 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 aboveidentified problems and shortcomings of the present state of nicotinic acid therapy 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 nicotinic acid or any compound which is metabolized by the body to form nicotinic acid 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 o apparent from the specification which follows, are accomplished by the invention as hereinafter described and claimed.

.According to a first embodiment of the invention, there is provided a starter kit, when used for acclimatising a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said kit comprising: sustained release nicotinic acid compositions comprising 7 x 375 mg nicotinic acid sustained release tablets; 7 x 500 mg nicotinic acid sustained release tablets, 7 x 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.

25 According to a second embodiment of the invention, there is provided the use of sustained release nicotinic acid tablets to acclimatise a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said use comprising the steps of administering as a single dose only once a day during the evening or at night as follows: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, followed by 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and followed by 750 mg nicotinic acid in a sustained release formulation each day for 7 days.

According to a third embodiment of the invention, there is provided a method of acclimatising a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said method comprising administering as a single dose only once a day during the evening or at night: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, followed by 500 mg nicotinic acid in a sustained release A477610DIspeci formulation each day for 7 days, and followed by 750 mg nicotinic acid in a sustained release formulation each day for 7 days.

Also herein disclosed is 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 by weight of hydroxypropyl methylcellulose per hundred parts by weight of tablet or formulation.

Also disclosed is 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 ofhydroxypropyl methylcellulose.

Also disclosed is 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 S. dose is given once per day in the evening or at night, combined with a pharmaceutically 20 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 25 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. The other compounds specifically include, but are not limited to the following: nicotinyl alcohol tartrate, d-glucitol hexanicotinate, aluminum nicotinate, niceritrol and d,l-alpha-tocopheryl nicotinate. Each such compound will be collectively referred to hereinbelow by "nicotinic acid".

A477610DIspeci -6- 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 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 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 -7a 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 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 l-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.

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.

-8- Examples of various embodiments of the present invention will now be further illustrated with reference to the following examples.

General Experimental 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 TABLE IA hereinbelow.

TABLE IA Test Tablet Composition Ingredient 375 m 500 m 750 m 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 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 -9matrix delivery system can be modified depending on the type and molecular weight of hydrophilic polymer used.

A Niaspan® formulation consists of Niacin, Methocel® E 10M Premium, Povidone and Hystrene 5016 (stearic acid). Methocel® E1OM Premium is utilized as a controlled-release agent 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 l-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.

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 EO1M 7.4 8.1 8.9 Premium (Intragranular) 2.2 2.4 2.7 2.9 Providone Methocel EIOM 25.0 18.0 10.0 Premium (Extragranular) Hystrcnc 5016 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 .0.750" 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.

11 Niaspan@ Granulation Process Flow Chart Raw Materials Niacin Providone K90 Methocel E OM (Intragranular) Purfied Water Process Flow Granulate Equipment High shear granulator (Littleford FM 130) Fluid bed drier (Glatt fluid bed drier) Mill (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.

Niasnan® Tablet Process Flow Chart Raw Materials Process Flow i..

Methocel E1OM (Extragranular) Hystrene 5016 (Stearic acid) Niaspan® Tablet Blend Blend Milled Niaspan® granules with cxtragranular Methocel E10M and Hystrene 5016 Niaspan® Table Manufacture Compress Niaspan® Tablet Blend qI UIIIIIIIL Blender (Patterson-Kelley V-Blender) Rotary tablet press Niaspan® Tablet Process Description A Niaspan® tablet blend is manufactured by blending the Niaspan® granulation, extragranular Methocel E10M and Hystrene 5016. The quantities of each Niaspan® 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 of Niaspan® 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 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 kilogram kilogram 160.00 kg granulation (kg) granulation batch (kg) Niacin, USP Drug Substance 0.87 87.00 139.20 Povidinc, UPS Binder 0.03 3.00 4.80 Methocel USP, Controlled- 0.10 10.00 16.00 EIOM 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 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 FM 130 granulator, with choppers on, for approximately 1 minute. At the completion of the 1-minute pre-mix cycle, about 12.0±0.05kg 13 of 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.

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 0 C±5°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 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 EI0M 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.

Also in accordance with the present invention, a starter kit is provided for initial dosing and titration of a patient with a sustained release formulation of the present invention. Such a kit may contain, for example, 21 tablets in total at variant strengths for administration over a 21 consecutive day period to minimize and avoid any hepatotoxic and flushing effects associated with and to improve tolerance of the therapy. More particularly, the starter kit may include 7 nicotinic acid sustained release tablets at 375 mg, 7 nicotinic acid sustained replace tablets at 500 mg and 7 nicotinic acid sustained release tablets at 750 mg accompanied with instruction to take one tablet per day during the evening or at night beginning with the 375 mg strength tablets until gone, followed by the 500 mg strength tablets until gone, which is then followed by the 750 mg tablets until gone.

-14- Once the starter kit has been completed, the patient should be further titrated by starting the patient on the following regimen in which the nicotinic acid sustained release tablets are administered as a single dose only once a day during the evening or at night: 2 x 500 mg tablets for one month; 2 x 750 mg tablets for one month; 2 x 1000 mg tablets for one month; x 500 mg tablets for one month; 3 x 1000 mg tablets thereafter.

It of course should be understood, that after each dosage increase following completion of the starter kit as indicated above, the patient' lipid and liver enzyme profiles should be thoroughly examined to ensure that the patient is tolerating such therapy. In addition, the patient's lipid and liver enzyme profiles should be thoroughly checked before and upon completion of the starter kit, and that they should be continually and closely monitored throughout the entire therapeutic treatment.

It therefore should be appreciated by those versed in this art that the above-regimen represents one example as to how to titrate and treat a patient with hyperlipidemia in accordance with the present invention.

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.

Page(s) are claims pages They appear after the table listings TABLE 11 Patient Study Lipid Profile Data 11t. No.

GROUP A 2 3 4 s 6 7 8 9 11 Mean p-Value GROUP B 2 3 4 6 7 8 9 11 12 13 Total-C 1.1-C Apo 13 -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 -19.2 -32.2 -21.4 -19.9 -3.3 23.1 24.8 10.1 -2.9 -10.5 -20.0 17.4 -12.0 -27.0 -13.0 -10.0 -17.7 -25.9 -31.4 -7.4 1.1 -0 2 -9.4 -13.9 0.000 1- 13.9 -27.1 -35.7 -33.6 -24.6 -2.1 -32.6 34.0 12.0 -7.7 -18.8 -30.8 16.8

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

-24.4 -28.0 -35.6 -15.1 -29.4 Tn-i _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 -33.4 -60.4 -33.4 -20.8 -41.1 HDI,-C HDL- 22.0 NA 65.0 NA -9.1 NA 3.8 NA 11.1 NA 51.6 NA 12.5 NA 18.8 NA 9.2 NA 22.9 NA 44.3 NA 23.0 NA 0.0068 20.0 22.3 4.3 3.2 30.4 38.6 9.6 16.1 5.8 2.4 FROM STUDY 49.2 68.9 6.5 -6.8 20.7 -12.3 53.1 70.5 31.8 39.7 21.1 25.0 51.3 51.9

L~W

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

-81.9 -25.3 -17.4 -27.0 -22.4 -14.3

NA

40.6 -41.2

NA

-28.4 38.5 PATI.ENT WITHDREW -42.6 -58.6 -28.4 5.5 -16.8 -11.6 -28.0 -59.0 -25.3 -53.4 -30.4 11.7 -17.5 -17.5 16- TABLE II (Continued) Patient Study Lipid Profile Data Pt. No. TotaL-C L.-C Ao 3 HOL-C HD.C La 14 -9.4 -16.6 -32.0 -46.9 52.3 67.6 17.6 MEAN -8.7 -12.8 -32.2 -27.2 25.3 30.1 -17.9 p-Value 0.0002 <0.0001 0.0001 <0.001 <0.0001 0.0002 <0.0188 Combined -8.7 -13.3 Gp 13 -26.1 25.3 Gp B Gp 13 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 III-VII hereinbelow.

17- TABLE III THE EFFECT OF NIASPAN® THERAPY ON AST (SGOT) LEVELS (UIL) (1500 mgs doscd once-a-day at night) (n 28) Weeks of Therapy With NiaspanG® Baseline 2 Wks. 4 Wks. 8 Wks.

Reference Ranpe GROUP A 1 28 29 224 25 3 17 18 4 14 16 22 NA 6 21 17 7 17 17 8 20 21 9 16 16 18 21 11 21 21 GROUP B 123 25 2 20 20 3 15 20 4 25 22 23 21 6 PATIENT WITHDREW D)UE TO FLUSHING 7 21 18 8 18 19 9 Is 16 16 15 11 20 22 12 23 25 13 20 IS 0-s0 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 050 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-50 0-S0 0-50 18- 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® Pt# Baseline 2 Wks. 4 Wks. 8 Wks. Reference Range 14 18 25 20 18 0-50 Cornbiticd Mcan M98 20.4 208 21.1 Change From Baseline Level of Significance: p= 0 414 1 TABLE IV TilE EFFECT OF NIASPAN® THERAPY ON ALT (SGPT) LEVELS (UJL) (1500 mgs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan® Pt Baseline 2 k. 4 Wks, 8 ks Reference Range GROUP A 1 32 28 39 30 0-55 2 24 25 23 26 0-55 3 18 23 30 30 0-55 4 7 13 14 14 0-55 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 19- TABLE IV (Continued) THE EFFECT OF NIASPAN® THERAPY ON ALT (SGPT) LEVELS (UIL) (1500 mgs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan® Pt# Baseline 2 Wks, 4 Wks. Reference Ramg 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 4 2 4 14 15 21 13 20 26 23 17 DUE TO FLUSHING 16 18 20 17 5 11 10 14 12 18 18 20 NA 11 23 19 17.5 19.3 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 1.1% 9.0% +2.8% 20 TABLE V THE EFFECT OF NIASPAN® THERAPY ON ALKALINE PHOSPHATASE LEVELS (UJL) (1500 mgs dosed once-a-day at night) (n 28) Weeks of Therapy With Niaspan®g Pt# GROUP A 2 3 4 5 6 7 8 9 10 I1I Baseline 52 103 54 70 77 55 72 -55 53 74 18 2 Wks 56 100 45 68

NA

48 71 49 73 18 Reference Ran-ge 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140 20- 140

GROUPIB

1 73 67 89 2 82 64 72 3 73 69 72 4 37 36 37 65 53 54 6 PATIENT WITHDREW DUE TO FLUSHI-NG 7 64 58 58 8 79 78 65 9 94 92 101 20- 140 20- 140 20-140 20-140 20-140 20-140 20- 140 20-140 21 TABLE V (Continued) THE EFFECT OF NIASPAN® THERAPY ON ALKALINE PHOSPHATASE LEVELS (U/b) (1500 mngs dosed once-a-day at night) (n =28) Weeks of Therapy With Niaspan® Baseline 2 Wks 67 67 59 68 61 61.5 -6.1% 4Wks 70 63 59 66 59 63.3 -3.4% 8 Wks 65 72 63 64 64 Reference Range 20- 140 20- 140 20-140 20-140 20-140 13 14 Combined Mean Change From Baseline 64 72 66.5 65.8 +0.005% Level of Significance: p=0.0236 22 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® Baseline 4 Wk.

GROUJPA

1 5.2 5.0 2 4.0 4.6 3 6.3 7.0 4 3.1 4.6 5 3.4 NA 6 6.6 5.5 7 3.8 4.5 8 4.4 3.8 9 3.9 4.5 10 26 2.9 11 4.7 5.5 GROUP B 1 3.7 4.2 2 2.8 3.5 3 4.2 5.3 4 4.7 3.9 3.7 4.1 6 PATIENT WITH-DREW DUE TO 7 5.8 6.6 8 4.7 4.3 9 3.7 4 6 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

FLUSHING

6.6 5.4 5.1 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 23 TABLE VI (Continued) THE EFFEC'I'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, 4.6 5.4 4.82 +6.2% 4 Wks.

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 Reference HAMz 2.5-7.5 2.5-7.5 4.0-8.5 2.5-T.5 2.5-7.5 *p= 0 345 0 14 Combined Mean Change From Baseline 5.5 4.54 Level of Significance: p=.

34 -24- TABLE VH THE EFFECT OF NIASPAN® THERAPY ON FASTING GLUCOSE LEVELS (mg/dL) (n 28) Weeks of Therapy With Niaspan® Baseline 2 Wks 4 Wks 8 Reference Range GROUP A 1 114 122 123 2 101 105 107 3 99 98 109 4 100 118 94 89 NA 82 6 97 103 94 7 85 107 100 8 98 107 103 9 97 97 100 94 101 111 11 102 103 95 GROUP B 1 101 97 83 2 90 95 96 3 96 98 95 4 116 139 113 88 98 91 6 PATIENT WITHDREW DUE TO FLUSHING 7 106 114 118 8 95 106 106 9 81 92 84 108 117 122 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 TABLE VII (Continued) THE EFFECT OF NIASPAN® THERAPY ON FASTING GLUCOSE LEVELS (mg/dL) (n 28) Weeks of Therapy With Niaspan® Pt# Baseline 2 Wks 4 Ws. 8 Wks Reference Range 11 85 106 106 108 70-115 12 92 89 101 86 80-125 13 99 105 94 100 70-125 14 100 108 84 107 70-125 Combined 98.4 105.8 101.6 102.3 Mean Change From 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 V1II A Comparison of Changes in Liver Function Tests

DOSE

0 1 500 1000 -1 1500 2000 1 2500 13000 [TOTAL 1 [McKenney Sr' [AST 23 8 1 27.9 40.4 F 366 56.5 Ila f97.0 F 1 117 170 I 154 237 Ila 1408[_ [AST 24.3 j na I 23.7 j 7.5 26.6 276 127.8 I na J 98 113 109 114 114I_ _1 McKeniney SR [Niacin ALT F 256 1 29.5 36.3 39.0 59.1 NA I1o00__ __0 I 115 j 142 152 231 NA 391I Invention Dosage ALT F 21.4 na 18.7 22.6 21.3 22 4 [21 8 na 87 106 100 0 102 I_ McKenney SR Niacin ALK 1 95 j 106 OS 36 n[135 TABLE ViIl (Continued) A Comparison of Changes in Liver Function Trests

DOSE

0 [o 500 1000 1500 2000 2500 [3000 [TOTAL 1 100 112 111 143 na [142 Invention Dosage ALK [F 74 7 na 73.9 f 76.1 J 73.4 76.7 [78.0 F na 99 102 98103 1!04 [Drop [0 [2 [2 71 n 7 181 [o9[ 9I 30 n, 1 30 1[78 [Invention Dosage [Drop [0 0 0o 0t10 fo [n j j 26 67 97 35_ 1s 1512401 yer-- 1- 15 46 77 31 15 184 I 58 69 1 79 89 100 7 -28 a 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.

Journal 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 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 of LDL cholesterol, triglyceride and Lp(a) while increasing I-IDL 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 (5)

1. A starter kit, when used for acclimatising a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said kit comprising: sustained release nicotinic acid compositions comprising 7 x 375 mg nicotinic acid sustained release tablets; 7 x 500 mg nicotinic acid sustained release tablets, 7 x 750 mg nicotinic acid sustained release tablets; and a housing for containing said tablets.

2. The use of sustained release nicotinic acid tablets to acclimatise a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said use comprising the steps of administering as a single dose only once a day during the evening or at night as follows: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, followed by 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and followed by 750 mg nicotinic acid in a sustained release formulation each day for 7 days.

3. The use of nicotinic acid in a sustained release formulation in accordance with claim 2 comprising the further steps of administering: 1000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days; 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days; (f) :2000 mg of sustained release nicotinic acid as a single dose once daily during the evening S 20 or at night for approximately the following 30 days; 2500 mg of sustained release Snicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days, and 3000 mg of sustained release nicotinic acid as a single dose S..once daily thereafter.

A method of acclimatising a patient diagnosed with hyperlipidemia to nicotinic acid treatment for said condition, said method comprising administering as a single dose only once a day during the evening or at night: 375 mg of nicotinic acid in a sustained release formulation each day for 7 days, followed by 500 mg nicotinic acid in a sustained release formulation each day for 7 days, and followed by 750 mg nicotinic Sacid in a sustained release formulation each day for 7 days.

5. The method of claim 4, which further comprises administering: 1000 mg of S-sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days; 1500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following days; 2000 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days; 2500 mg of sustained release nicotinic acid as a single dose once daily during the evening or at night for approximately the following 30 days, and 3000 mg of sustained release nicotinic acid as a single dose once daily thereafter. Dated 17 June, 2004 Kos Life Sciences, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON A477610DIspeci