WO2008100249A1

WO2008100249A1 - Low flush niacin formulation

Info

Publication number: WO2008100249A1
Application number: PCT/US2007/003659
Authority: WO
Inventors: Jose G. Rocca; Yucun Zhu; Eugenio A. Cefali
Original assignee: Kos Life Sciences, Inc.
Priority date: 2007-02-13
Filing date: 2007-02-13
Publication date: 2008-08-21

Abstract

The invention relates to an extended release matrix formulation capable of being directly compressed into tablets comprising niacin, a release retarding agent, and other excipients. The resulting tablets of the invention demonstrate favorable release characteristics and a reduction in the incidences of cutaneous flushing commonly associated with niacin treatment.

Description

LOW FLOSH NIACIN FORMULATION

Field of the Invention

Background of the Invention

Niacin (nicotinic acid, also known as 3-pyridinecarboxylic acid, chemical formula QH5NO₂) is known to have benefits associated with the treatment of hypercholesterolemia because it increases levels of high density lipoproteins (HDL) and lowers levels of total serum cholesterol low density lipoproteins (LDL) and triglycerides.

Although niacin is known to provide a very beneficial effect on blood lipids, with the exception of Niaspan®, widespread use of niacin is limited due to the high incidence of "flush" that often occurs with higher doses of niacin needed for effective lipid treatment. Flushing is a term generally used to describe prostaglandin-mediated vasodilatation. As a result, an individual experience flushing may develop a visible, uncomfortable hot or flushed feeling upon administration of niacin. While certain materials and/or formulations have been suggested for avoiding or reducing cutaneous flushing (see US Pat. Nos.4,956,252, 5,023,245 and 5,126, 145), this unwanted side-affect remains an issue with wide scale utilization of niacin products. Therefore, there is a need in the pharmaceutical arts for an extended release nicotinic acid formulation that provides reduced levels of cutaneous flushing over existing niacin formulations.

Summary of the Invention

The present invention provides for an direct compression, extended release (ER) matrix tablet formulation comprising niacin and a release retarding agent. In particular, the present invention provides a pharmaceutical tablet comprising:

(a) about 70% to about 95% w/w of niacin;

(b) about 10% to about 25% w/w of a release retarding agent;

(c) about 1.3% to about 4.3% w/w of a binder, and

(d) about 0.5% to about 1.5% w/w of a lubricant.

Further, the present invention provides for method of preparing the extended release niacin tablets which comprises the steps of

(a) blending a mixture of about 70% to about 95% w/w of niacin, about 10% to about 25% w/w of a release retarding agent, about 1.3% to about 4.3% w/w of a binder, and about 1.3% to about 4.3% w/w of a lubricant;

(b) compressing the mixture of step (a) into a tablet..

Also provided is a method of reducing flushing associated with niacin treatment therapy, wherein said method comprises using the extended release niacin tablets forms of the present invention

The present invention further provides a once daily niacin pharmaceutical dosage form, said dosage form providing, when administered as a single dose of two 1000 mg tablets to a subject, in vivo NUA plasma profile characterized by at least one of the following

(a) a mean maximum plasma concentration (Cmax) in the range of about 1357 ng/mL to about 3517 ng/mL; and (b) a mean area under the plasma concentration versus time curve from time zero to time last (AUQ_asl) of about 4971 ng/mL to about 17591 ng/mL.

Brief Description of the Drawings

Figure 1 is illustrates a flow-diagram of a direct compression manufacturing process for preparing the tablet formulations in accordance with, an embodiment of the invention.

Figure 2 is a chart illustrating a reduction in the overall intensity of flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®)

Figure 3 is a chart illustrating a reduction in the overall duration of flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Figure 4 is a chart illustrating a reduction in subjects experiencing flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Figure 5 is a chart illustrating a reduction in the incidence of multiple flushing symptoms for subjects using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Figure 6 is a chart illustrating the mean plasma concentrations of niacin using the extended-release niacin tablets of the present invention.

Figure 7 is a chart illustrating the mean plasma concentrations of nicotinuric acid (NUA) using the extended-release niacin tablets of the present invention. Detailed Description

The extended release matrix tablet formulations of the present invention include niacin as an active ingredient and a hydrophilic polymer matrix for achieving controlled, extended release of the active ingredient, i.e., a release retarding agent

A hydrophilic matrix, controlled-release system involves polymer wetting, polymer hydration, gel formation, swelling and polymer dissolution. Soluble drugs in the matrix also wet, dissolve and diffuse out of the matrix. Although the mechanism by which soluble drugs are released in matrix tablets are dependent on many variables, the main principle is that the water-soluble polymer, present throughout the tablet, hydrates on the outer tablet surface to form a gel layer. As water permeates into the tablet, the gel layer increases in thickness and the soluble drug diffuses through the gel layer. During the life of the ingested tablet, the rate of drug release is determined by diffusion of the soluble drug through the gel and by the rate of tablet erosion.

The hydrophilic component of the present invention may be any hydrophilic release retarding agent that demonstrates favorable swelling and gelling properties, such as those known to those skilled in the art.

The release retarding agent will typically be present in the tablets of the present invention at a concentration of about 10% to about 25% w/w (percent weight relative to total weight of the formulation), preferably about 12.5% to about 20% w/w, more preferably about 14% to about 18% w/w.

Examples of suitable release retarding agents include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyhnethyl cellulose (HPMC or hypromellose), methylceUulose (MC), hydroxyethyf cellulose (HEC) and polyvinyl pyrrolidone (PVP)₃ xanthan gum, as well as mixtures of these release retarding agents. Preferred are medium- viscosity hydroxypropylmethyi cellulose and medium-viscosity polyvinyl alcohol.

Preferably the release retarding agent is hydroxypropylmethyi cellulose. HPMC has a polymeric backbone of cellulose, a natural carbohydrate that contains a basic repeating structure of anhydrogiucose units. The hydration rate (i.e., the drug release rate) of HPMC will differ as a result of varying proportion of the two chemical substituents, hydroxypropyl and methyl substitution, attached to the cellulose backbone of HPMC The hydroxypropyl substitution is relatively hydrophilic in nature and greatly contributes to the rate of hydration, while the methoxyl substitution is relatively hydrophobic in nature. The amount of substituent groups on the anhydrogiucose units of cellulose can be designated by the average number of substituents groups attached to a single anhydrogiucose ring, a concept commonly known to those skilled in the art as 'degree of substitution". See "Methocel® Cellulose Ethers Technical Handbook, Dow Chemical Company. In one embodiment of the invention, the HPMC release retarding agent has a methoxyl degree of substitution of about 1.2 to about 2.0 and a hydroxypropyl molar substitution of about 0.1 to about 0.3, preferably a methoxyl degree of substitution of about 1.4 to about 1.9% and a hydroxypropyl molar substitution of about 0.21 to about 0.23, more preferably a methoxyl degree of substitution of about 1.4 to about 1.45 and a hydroxypropyl molar substitution of about 0.21 to about 0.215.

Additionally, hydroxypropylmethyi cellulose polymers are commercially available in different viscosity grades. These include, for example, 4000 and 15000 mPas (1 Centipoise (cps) = 1 mPa s (Millipascal Second)) viscosity grades of Methocel K, i.e. Methocel K4M and Methocel Kl 5M, available from the Dow Chemical Co, USA, and 4000, 15,000 and 39000 mPas viscosity grades of Metalose 90 SH, available from Shin Etsu Ltd, Japan. In an embodiment of the invention, HPMC viscosity (determined in water at 20° C, with a concentration of 2%, e.g., ASTM D2363) is about 11,000 to about 22,000 Millipascal (mPas), preferably about 13,000 to about 18,000 MiUipascal (mPas).

Niacin, a water soluble medicament, is commercially available as fine white crystals, granular or white crystalline powder. Niacin will typically be present in the tablets of the present invention at a concentration of 70% to 95% w/w, preferably 70% to 90% w/w, more preferably 78% to 82% w/w.

The tablets of the present invention further comprise a binder. The binder may be any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone (also known as PVP, povidone, polyvidone), hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used. In an embodiment of the invention, the binder comprises about 1.3% to 4.3% w/w of the total weight of the tablet, preferably about 2.0% to 3.25% w/w, more preferably about 2.5% to 3.0% w/w.

Tn addition, the tablets of the present invention comprise a lubricant. The lubricant may be hydrophobic or hydrophilic and include lubricants commonly known to those in the art, such as, but not limited to talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like. Preferably, the lubricant is stearic acid. Lubricant addition helps to reduce the friction between the die wall and tablet formulation during compression and aids in the flow of powder (i.e., the flow of mixed formulation into the hopper and die) and helps to prevent adhesion of tablet material to processing equipment. In one embodiment, the tablet formulations of the invention comprise about 0.5% to 1.5% w/w of a lubricant, preferably about 0.75% to 1.25% w/w, more preferably, about 0.85% to 1.15% w/w, more preferably, about 0.95% to 1.05% w/w.

The extended release tablet formulations of the invention may further include a coating, such as an Opadry® type coating, as are known to those skilled in the art, and may be applied from solution (e.g., aqueous) or suspension using any known means, such as a fluidized bed coater (e.g., Wurster coating) or pan coating system. In one embodiment of the invention, coating is a color coating having from about 1.5 to about 8.0% weight gain, preferably from about 1.75 to about 5.0% weight gain.

Figure 1 illustrates a flow-diagram of a direct compression manufacturing process for preparing the tablet formulations in accordance with an embodiment of the invention.

The following examples serve to better illustrate, but not limit, multiple embodiments of the invention.

EXAMPLE I

The following formulation was used in this example:

TABLE 1

For a 20 kg batch size, delumped niacin granular and the excipients were weighed according to the above formula and then added into an 8 quart blender and blended for 10 minutes. The resultant granular composition was directly compressed into tablets using a BWI Manesty Beta Press with a 19 mm length oval tooling at 30 kN. Optionally, the stearic acid or povidone may be screened through a mesh screen, such as a 40 mesh screen, and mixing steps (one or two) and mixing time (10, 15 or 20) can be varied in alternate embodiments.

The resulting compressed tablets were coated with a 2% weight gain color coat of Opadry® Orange 03B93199. The coating conditions were as follows:

TABLE 2

The coated niacin 1000 mg direct compression tablets were found to be stable for three months at 40°C/75% relative humidity (RH) and 25°C/60% RH by comparing the niacin assay, niacin dissolution, moisture of the tablets and the physical appearance of the coated tablets prior to and following the stability study. Using the processes described herein, 500 mg and 750 mg extended-release direct compression tablets (coated or uncoated) may be prepared having content concentrations illustrated in Tables 3 and 4 below.

TABLE 3: 500 MG TABLETS

For the 500 mg and 750 mg tablets, delumped niacin granular and the excipients would be weighed according to the component concentrations illustrated in Tables 2 and 3 and then blended in a suitable blender or mixer for an appropriate time to adequately mix the components. The resultant granular compositions could then be directly compressed into tablets using a suitable press, such as the BWT Martesty Beta Press described above, to form a 500 mg or 750 mg tablet as desired. Optionally, the 500 mg and 750 mg tablets may be coated, such as with a color coat, as is known in the art.

EXAMPLE 2

Comparative Incidence of Flushing Between Coated, Extended-Release 1000 mg Niacin Direct Compression Matrix Tablets and 1000 mg Niaspan®

The present study was conducted to compare the incidence of flush associated with the administration of 1000 mg coated, extended-release niacin tablets of the present invention versus commercially available 1000 mg Niaspan® tablets (uncoated). In particular the study measured the incidence of flushing associated with the administration of niacin as a single, 2000 mg dose of a) two 1000 mg coated, extended-release niacin tablets of the present invention plus two uncoated placebo tablets (Test), b) two commercially available 1000 mg Niaspan® tablets plus two coated placebo (Reference), c) two coated placebo tablets plus 2 uncoated placebo tablets (Control). Intensity and duration of symptoms associated with the first flushing event or episode, intensity and duration of the first flushing episode overall, and of subsequent flushing symptoms was also assessed. A flushing event or episode was described as one or more of the following concurrent flushing symptoms: redness, warmth, tingling, and itching.

The study was a randomized, single-center, double-blind, double-dummy, randomized, placebo-controlled, single-dose, three-way crossover study in 156 healthy, non-smoking men, 30 to 70 years (yrs)-of-age, inclusive. Dropouts were not replaced. Study medication was administered orally with a minimum washout period of 7 days between each treatment administration: 2000 mg niacin on two separate occasions and placebo control once (uncoated and coated). Each subject received either two 1000 rag reformulated, coated niacin extended- release tablets (tablets of the invention) plus two uncoated placebo tablets (Treatment A), two 1000 mg Niaspan® tablets plus two coated placebo tablets (Treatment B), or two uncoated placebo tablets similar looking to Niaspan®, plus 2 coated matching placebo tablets (Treatment C), in a three-way crossover design. Each dose was administered with 240 milliliters (mL) of water after a low-fat snack at approximately 22:00 in the evening. Subjects received meals according to Sponsor-provided menus during each treatment period and no other medications, vitamins, or herbal and/or nutritional supplements were permitted during the study. Meal composition and start time were the same for each treatment period. The snack was consumed in its entirety within a 15-mimite (min) period before study drug administration. Study drug was administered within 15 min of the start of the snack. These conditions are consistent with recommended dosing instructions for Niaspan®.

On an hourly basis for up to 8 hrs post-dose, subjects were prompted to assess the presence or absence of symptoms associated flushing (redness, warmth, tingling, and/or itching). The subjects were prompted to record start and stop times of the flushing symptom and to mark a vertical line on an horizontal, visual analog scale (ranging from none on the left to intolerable on the right — a VAS scale of 0 to 100) to rate the intensity of each symptom.

Each, subject also rated intensity overall of the first flushing event or episode, defined as beginning at the start time of the first of one or more concurrent flushing symptoms to occur in a treatment period. The end time of that flushing episode was defined as the last stop time of one or more concurrent flushing symptoms occurring in that episode that was also followed by a symptom-free period lasting a minimum of 30 min. After rating intensity overall of the first flushing episode, the subject characterized each recurrence of a flushing symptom in the same study period by entering the start/stop times and marking a vertical line on a visual analog scale for symptom intensity. No additional assessments of intensity were made.

Summary and Analysis of the Overall Intensity and Duration of the First Flushing Event

Overall Intensity of First Flushing Event (VAS)

Overall Duration of First Flushing Event (min.)

Note: Subjects who did not have intensity or duration for a particular study period were excluded from the paired analysis. a The flushing analysis population is defined as subjects who received at least one dose of study medication, and experienced at least one flushing event, or who were evaluated without a flushing event for 8 hours and participated in at least two study periods.

\ TEST: 2 X lOOOmg coated, reformulated niacin extended-release tablets plus 2X uncoated placebo tablets (Treatment A). REF: 2 X 1000 mg Niaspan© tablets plus 2X coated placebo tablets (Treatment B)

TEST vs. REF: Matched paired T-Test (O.0001).

The percentages in reduction disclosed in the attached Figures were calculated using median values (e.g., for intensity: [(33/57)-lj X 100 = -42.1%).

As can be seen in Figure 2, there was a 42% reduction in the overall intensity of flush (p < 0.0001) using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Figure 3 illustrates a 43% reduction in the overall duration of flush (p < 0.0001) using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Summary and Analysis of the Number of Subjects Who Flushed or did not Flush³

a All subjects who participated in both TEST and REF treatment periods b TEST: 2 X 1 OOOmg coated, reformulated niacin extended-release tablets plus 2 X uncoated placebo tablets; REF: 2 X lOOOmg Niaspan® tablets plus 2 X coated placebo tablets. Mcnemar's Test (0.0027) comparing the number of subjects who flushed on one treatment but not the other, for both treatments.

Figure 4 illustrates a 9% reduction in subjects experiencing flush (p < 0.0027) using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).

Summary and Analysis of the Presence or Absence of Flushing Symptoms for the First Flushing Event"

^a- The flushing analysis population is defined as subjects who received at least one dose of study meciation, and experienced at least one flushing event, or who were evaluated without a flushing event for 8 hours and participated in at least two studies. b- TEST: 2 X lOOOmg coated, reformulated niacin extended-release tablets plus 2 X uncoated placebo tablets (Treatment A); REF 2 X 1000 mg Niaspan® tablets plus 2 X coated placebo tablets (Treatment B). c- McNemar's Test.

Figure 5 illustrates a reduction in the incidence of multiple flushing symptoms for subjects using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®). In particular, the extended-release niacin tablets of the present invention provides an 17.4% reduction in redness (p < 0.0016), a 14.2% reduction in incidences of warmth (p < 0.0163), a 24.1 % reduction in incidences of tingling (p < 0.0039) and a 25.6% reduction in incidences of itching (p < 0.0015).

EXAMPLE 3

In another study, the 1000 rag coated, extended-release niacin tablets of the present invention were administered to individuals/study groups in order to evaluate the bioavailability of the niacin tablets.

This bioavailability study was a randomized, single-center, open-label, single-dose, two- way crossover in 44 healthy, non-smoking male and female volunteer subjects, 40 to 70 years- of-age, inclusive. Drop-outs were not replaced. Each eligible subject received two treatments (Treatment A or Test, and Treatment B or Reference), which were separated by a minimum 10-day washout, in two periods. In Treatment A, subjects received two 1000 mg coated reformulated extended-release, niacin tablets (made in accordance with the present invention- Test) and in Treatment B subjects received two of the 1000 mg uncoated reformulated, extended-release niacin tablets (made in accordance with the present invention-Reference).

Each dose was administered with 24OmL of water after a low-fat snack beginning at approximately 22:00 hours (hrs) on Day 1 of each period. Subjects received meals according to sponsor-provided menus during each treatment period. No other medications, vitamins, herbal or nutritional supplements were permitted during the study. Plasma Collection and Analysis

Serial blood samples were collected within 30 min prior to dosing and through 24 hrs after dosing in each period (15 samples/treatment). Each blood sample was collected into one 17-mL vacutainer containing sodium heparin and was allowed to cool in an ice-chip and water bath for a minimum of 5 min after collection. Samples were centrifuged at 4° C at approximately 3000 rpm for 15 min to separate the plasma. Samples were then stored frozen at approximately -20° C until shipped on dry ice to an independent contractor for niacin and NUA analysis.

Niacin and nicotinuric acid (NUA) concentrations was analyzed by validated liquid chromatography tandem mass spectroscopy (LC/MS/MS). Both niacin and NUA concentrations were obtained from the same injection. The lower limit of quantitation (LLQ) for both niacin and NUA was 2 ng/mL in plasma. Quality control samples were evaluated with each analytical run.

Urine Collection and Analysis

Urine was collected for the following intervals: -24 to -18, -18 to -12, -12 to -6, -6 to 0 hrs {prior to dosing), and 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72, 72 to 96 hrs after dosing (for a total of 11 collections).

Urine was collected and transferred into plastic containers equipped with tightly fitting lids. Collected urine was kept refrigerated or in an ice-water bath during the collection interval. The collection containers were labeled to identify the subject number and initials, collection interval, and protocol number. The empty containers were weighed to the nearest tenth of a gram (e.g., 100.1 g) and this was written on the container and documented on the lab's source document worksheets. At the end of each interval, the total weight of the container and the collected urine was measured to the nearest tenth of a gram and recorded. The weight of the urine was derived by subtracting the weight of the empty container from the total weight of the container plus the urine. In some cases, the volume of urine during a given collection interval exceeded the capacity of a single container; therefore a second container was required to obtain a complete urine collection. The start and stop date(s) and times of each urine collection interval were also recorded. Samples were stored frozen at approximately -20^°C until shipped on dry ice an independent contractor for analysis.

Urine samples were analyzed for concentrations of niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) by validated LC/MS/MS; Urine niacin and NUA concentrations were obtained from the same injection while MNA and 2-PY concentrations were obtained from the same injection. In urine the LLQ values were 20 ng/mL for niacin and 200 ng/mL for MJA. MNA and 2PY had LLQ values of 500 ng/mL and 2500 ng/mL, respectively. Quality control samples were evaluated with each analytical run.

For urine analyses, a specific gravity of 1 g/mL was used to convert urine weights to volumes. This was based on a previous study with Niaspan® where the mean specific gravity measured in 962 samples was 1.009 g/mL and the maximum specific gravity measured in 962 samples was 1.025 g/mL.

Data from subjects providing sufficient information to calculate PK parameters for at least one treatment were included in the PK analysis. For niacin and NUA in plasma, the following PK parameters were calculated for each subject following administration of each treatment:

For niacin and NUA in plasma:

• Cmax: the maximum concentration observed

• Tmax-' the time of the maximum observed concentration

• AUC|_ast: the area under the concentration-time profile from time 0 to the last measurable (non-zero) concentration by the linear trapezoidal rule

For niacin and niacin metabolites (NUA, MNA, and 2-PY) in urine:

• Recovery for all four analytes combined (i.e., total recovery)

Statistical analysis of bioavailability data for the Test and Reference included the construction of 90% confidence intervals for Test/Reference (Treatment A/Treatment B) treatment ratios of natural log-transformed C_ma_X for NUA and total urine recovery data to determine bioequivalence (BE) between Test and Reference. The ratio and confidence intervals were obtained from the ANOVA model with treatment, period, and treatment sequence as fixed effects, and subject within sequence as a random effect. Confidence intervals within the conventional 80 to 125% limits for NUA C_niax and total amount of niacin and metabolites excreted in urine were required to conclude BE. Table 5 illustrates mean PK parameters for plasma niacin.

Table 5 : Niacin Plasma Parameters

The plots of mean, plasma concentrations of niacin by treatment are shown in Figure 6.

Table 6 below illustrates the mean (SD=standard deviation) and statistical results for plasma NUA alone, and total urinary recovery of niacin and three metabolites (NUA, MNA, and 2-PY).

Table 6: NUA Plasma Parameters and Total Urinarv Recovery

" Parameters used to define Niacin bioequivalence b Recovery of niacin, NUA, MNA, and 2PY combined. c Supportive data for bioequivalence

Plots of mean plasma concentrations of NUA are shown in Figure 7.

As shown in the above table the 90% CI for the natural-log transformed test to reference ratios of the primary bioequivalence variables, NUA C_max and Total recovery of niacin and metabolites were within 80 to 125%. The test formulation (coated reformulated 1000 mg extended release niacin tablet) is hence bioequivalent to the reference formulation (coated reformulated 1000 mg extended-release niacin tablet).

Formulations within the scope of the invention are those that are deemed bioequivalent to the formulations of the invention based on ratios of natural log-transformed Cma_x for NUA and total urine recovery data within standard 80% to 125% intervals (See for example, Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations, U.S. Department of Health & Human Sercices, Food and Drug Administration, CDER₅ March 2003)^". As is known to those skilled in. the art, such formulations are compared to reference formulations (such as those described herein or the embodiments of the invention described herein) under the same analytical conditions (e.g., analytical and technical conditions for urinary analysis) wherein the reference formula is used as a control.

While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications, and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims. AH patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

Claims

We Claim:

1. A 1000 mg niacin dosage form comprising:

(a) about 78% to about 82% w/w of niacin;

(b) about 14% to about 18% w/w of hydroxypropyl methylcellulose having a methoxyl degree of substitution of about 1.4% to about 1.45% and a hydroxypropyl molar substitution of about 0.21% to about 0.215%.;

(c) about 2.5% to about 3.0% w/w polyvinyl pyrrolidone, and

(d) about 0.95% to about 1.05% w/w stearic acid.

2. The pharmaceutical tablet of claim 1 wherein said tablet, when administered as a single dose of two 1000 mg tablets to a subject, provides an in vivo NUA plasma profile characterized by at least one of the following

(a) a mean maximum plasma concentration (Cmax) in the range of about 2437 ng/mL; and

(b) a mean area under the plasma concentration versus time curve from time zero to time last (AUQasO of about 11199 ng/mL.

3. A pharmaceutical tablet comprising:

(e) about 70% to about 95% w/w of niacin;

(f) about 10% to about 25% w/w of a release retarding agent;

(g) about 1:3% to about 4.3% w/w of a binder, and (h) about 0.5% to about 1.5% w/w of a lubricant.

4. The pharmaceutical tablet of claim 3 wherein said tablet is a 1000 mg extended- release niacin tablet formulation.

5. The pharmaceutical tablet of claim 3 wherein the release retarding agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC or hypτomellose), methylcellulose (MC), hydroxyethyl cellulose (HEC), polyvinyl pyrroHdone (PVP) and xanthan gum, or a mixture thereof.

6. The pharmaceutical tablet of claim 5 wherein the release retarding agent is hydroxypropyl methylcellulose.

7. The pharmaceutical tablet of claim 6 wherein the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.2% to about 2.0% and a hydroxypropyl molar substitution of about 0.1% to about 0.3%.

8. The pharmaceutical tablet of claim 7 wherein the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.4% to about 1.9% and a hydroxypropyl molar substitution of about 0.21% to about 0.23%.

9. The pharmaceutical tablet of claim 6 wherein the hydroxypropyl methylcellulose is a has a methoxyl degree of substitution of about 1.4% to about 1.45% and a hydroxypropyl molar substitution of about 0.21% to about 0.215%.

10. The pharmaceutical tablet of claim 7 wherein the hydroxypropyl methylcellulose has a viscosity of about 11,000 to about 22,000 Millipascal (mPas).

11. The pharmaceutical tablet of claim 7 wherein the hydroxypropyl methylcellulose has a viscosity of about 13,000 to about 18,000 Millipascal (mPas).

12. The pharmaceutical tablet of claim 3 further comprising a coating.

13. The pharmaceutical tablet of claim 12 wherein said coating is a color coating having from about 1.5 to about 8.0% weight gain.

14. The pharmaceutical tablet of claim 13 wherein said coating is a color coating having from about 1.75 to about 5.0% weight gain.

15. The pharmaceutical tablet of 6 wherein said binder is selected from, the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate and waxes, or a mixture thereof.

16. The pharmaceutical tablet of claim 15 wherein said binder is polyvinylpyrrolidone.

17. The pharmaceutical tablet of claim 6 wherein said lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oils, or a mixture thereof.

18. The pharmaceutical tablet of claim 17 wherein said lubricant is stearic acid.

19. The pharmaceutical tablet of claim 3 comprising:

(a) about 76% to about 90% w/w of niacin;

(b) about 12.5% to about 20.0% w/w of a release retarding agent;

(c) about 2.0% to about 3.25% w/w of a binder, and

(d) about 0.75% to about 1.25% w/w of a lubricant.

20. The pharmaceutical tablet of claim 19 comprising:

(a) about 78% to about 82% w/w of niacin;

(b) about 14% to about 18% w/w of a release retarding agent;

(c) about 2.5% to about 3.0% w/w of a binder, and

(d) about 0.85% to about 1.15% w/w of a lubricant.

21. The pharmaceutical tablet of claim 20 comprising about 0.95% to about 1.05% w/w of a lubricant.

21. A once daily niacin pharmaceutical dosage form, said dosage form providing, when administered as a single dose of two 1000 mg tablets to a subject, in vivo NUA plasma profile characterized by at least one of the following

(c) a mean maximum plasma concentration (Cmax) in the range of about 1357 ng/mL to about 3517 ng/mL; and

(d) a mean area under the plasma concentration versus time curve from time zero to time last (AUQ_ast) of about 4971 ng/mL to about 17591 ng/mL.

22. The once daily niacin pharmaceutical dosage form of claim 21, said dosage form providing an in vivo NUA plasma profile characterized by at least one of the following

(b) a mean area under the plasma concentration versus time curve from time zero to time last (AUCi_ast) of about 11199 ng/mL.

23. The once daily niacin dosage form of claim 21 wherein said dosage form is dosed once a day in the evening.

24. The once daily niacin dosage form of claim 21 wherein said 1000 mg tablet comprises

(a) about 70% to about 95% w/w of niacin;

(b) about 10% to about 25% w/w of a release retarding agent;

(c) about 1.3% to about 4.3% w/w of a binder, and

(d) about 0.5% to about 1.5% w/w of a lubricant

25. The once daily niacin dosage form of claim 24 wherein said 1000 mg tablet comprises

(a) about 76% to about 90% w/w of niacin;

(b) about 12.5% to about 20.0% w/w of a release retarding agent; <c) about 2.0% to about 3.25% w/w of a binder, and

(d) about 0.75% to about 1.25% w/w of a lubricant.

26. The once daily niacin dosage form of claim 25 wherein said 1000 mg tablet comprises

(a) about 78% to about 82% w/w of niacin;

(b) about 14% to about 18% w/w of a release retarding agent;

(c) about 2.5% to about 3.0% w/vv of a binder, and

(d) about 0.85% to about 1.15% w/w of a lubricant.

27. The once daily niacin dosage form of claim 26 wherein said 1000 mg tablet comprises about 0.95% to about 1.05% w/w of a lubricant.

28. The once daily niacin dosage form of claim 26 wherein the release retarding agent is hydroxypropyl methylcellulose and the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.2% to about 2.0% and a hydroxypropyl molar substitution of about 0.1% to about 0.3%.

29. The once daily niacin dosage form of claim 28 wherein hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.4% to about 1.9% and a hydroxypropyl molar substitution of about 0.21% to about 0.23%.

30. The once daily niacin dosage form of claim 29 wherein the hydroxypropyl methylcellulose is a has a methoxyl degree of substitution of about 1.4% to about 1.45% and a hydroxypropyl molar substitution of about 0.21% to about 0.215%.

31. The once daily niacin dosage form of claim 28 wherein the hydroxypropyl methylcellulose has a viscosity of about 11,000 to about 22,000 Millipascal (mPas).

32. The once daily niacin dosage form of claim 31 wherein the hydroxypropyl methylcellulose has a viscosity of about 13,000 to about 18,000 Millipascal (mPas).

33. The once daily niacin dosage form of claim 24 further comprising a coating.

34. The once daily niacin dosage form of claim 33 wherein said coating is a color coating having from about 1.5 to about 8.0% weight gain.

35. The once daily niacin dosage form of claim 34 wherein said coating is a color coating having from about 1.75 to about 5.0% weight gain.

36. A once daily niacin pharmaceutical dosage form, said dosage form providing, when administered as a single dose of two 1000 mg tablets to a subject, provides an in vivo niacin plasma profile characterized by at least one of the following

(a) a mean maximum plasma concentration (Cmax) in the range of about 5052 ng/mL; and

(b) a mean area under the plasma concentration versus time curve from time zero to time last (AUC_Iast) of about 12444 ng/mL.

37. A method of reducing flushing associated with niacin treatment therapy, said method comprising administering a once daily pharmaceutical dosage form comprising

(a) about 70% to about 95% w/w of niacin;

(b) about 10% to about 25% w/w of a release retarding agent;

(c) about 1.3% to about 4.3% w/w of a binder, and (d) about 0.5% to about 1.5% w/w of a lubricant.

38. The method of claim 37 where said once daily dosage form comprises two 1000 mg tablets.

39. The method of claim 37 wherein said tablet is a 1000 mg tablet comprising

(a) about 76% to about 90% w/w of niacin;

(b) about 12.5% to about 20.0% w/w of a release retarding agent;

(c) about 2.0% to about 3.25% w/w of a binder, and

(d) about 0.75% to about 1.25% w/w of a lubricant.

40. The method of claim 39 wherein said 1000 mg tablet comprises

(a) about 78% to about 82% w/w of niacin;

(b) about 14% to about 18% w/w of a release retarding agent;

(c) about 2.5% to about 3.0% w/w of a binder, and

(d) about 0.85% to about 1.15% w/w of a lubricant.

41 The method of claim 40 wherein said 1000 mg tablet comprises about 0.95% to about 1.05% w/w of a lubricant.

42. The method of claim 37 wherein the release retarding agent is selected from the group consisting of hydroxypropyl cellulose (HPC)₅ hydroxypropylmethyl cellulose (HPMC or hypromellose), methylceliulose (MC), hydroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP) and xanthan gum, or a mixture thereof.

43. The method of claim 42 wherein the release retarding agent is hydroxypropyl mcthylcellulose and the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.2% to about 2.0% and a hydroxypropyl molar substitution of about 0.1% to about 0.3%.

44. The method of claim 43 wherein the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.4% to about 1.9% and a hydroxypropyl molar substitution of about 0.21% to about 0.23%.

45. The method of claim 44 wherein the hydroxypropyl methylcellulose is a has a methoxyl degree of substitution of about 1.4% to about 1.45% and a hydroxypropyl molar substitution of about 0.21% to about 0.215%.

46. The method of claim 43 wherein the hydroxypropyl methylcellulose has a viscosity of about 11,000 to about 22,000 Millipascal (mPas).

47. The method of claim 46 wherein, the hydroxypropyl methylcellulose has a viscosity of about 13,000 to about 18,000 Millipascal (mPas).

48. The method of claim 37 further comprising a coating.

49. The method of claim 48 wherein said coating is a color coating having from about 1.5 to about 8.0% weight gain.

50. The method of claim 49 wherein said coating is a color coating having from about 1.75 to about 5.0% weight gain.

51. A method of preparing a direct compression niacin tablet comprising the steps of

(b) compressing the mixture of step (a) into a tablet.

52. The method of claim 51 wherein said niacin tablet is a 1000 mg niacin dosage formulation.

53. The method of claim 51 further comprising coating the tablet.

54. The method of claim 53 wherein said coating is a color coating having from about 1.5 to 8.0% weight gain.

55. The method of claim 54 wherein said color coating has from about 1.75 to 5.0% weight gain.

56. The method of claim 54 wherein said release retarding agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC or hypromellose), methylcellulose (MC), hydroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP) and xanthan gum, or a mixture thereof.

57. The method of claim 54 wherein said binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulosc, polymethacrylate and waxes, or a mixture thereof.

58. The method of claim 54 wherein said lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oils, or a mixture thereof.

59. The method of claim 54 wherein said tablet comprises about 70% to about 90% w/w of niacin, about 12.5% to about 20% w/w of a release retarding agent, about 1 ,3% to about 4.3% w/w of a binder, and about 1.3% to about 4.3% w/w of a lubricant.

60. The method of claim 59 wherein said tablet comprises about 78% to about 82% w/w of niacin, about 14% to about 18% w/w of a release retarding agent, about 1.3% to about 4.3% w/w of a binder, and about 1.3% to about 4.3% w/w of a lubricant.

61. The method of claim 51 wherein said release retarding agent is hydroxypropylmethyl cellulose, said binder is polyvinylpyrrolidone, said lubricant is stearic acid and wherein hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.2% to about 2.0% and a hydroxypropyl molar substitution of about 0.1% to about 0.3%.

62. A direct compression 500 mg niacin extended-release tablet formulation comprising:

(a) about 65% to about 85% w/w of niacin;

(b) about 20% to about 32% w/w of a release retarding agent;

(c) about 2% to about 3% w/w of a binder, and

(d) about 0.75% to about 1.25% w/w of a lubricant.

63. The direct compression 500 mg niacin extended-release tablet formulation of claim 62comprising:

(a) about 68% to about 75% w/w of niacin;

(b) about 24% to about 29% w/w of a release retarding agent;

(c) about 2.25% to about 2.75% w/w of a binder, and

(d) about 0.95% to about 1.05% w/w of a lubricant.

64. The direct compression 500 mg niacin extended-release tablet formulation of claim bb further comprising a coating wherein said coating has from about 1.5 to about 8.0% weight gain.

65. A direct compression 750 mg niacin extended-release tablet formulation comprising:

(a) about 74% to about 80% w/w of niacin;

(b) about 15% to about 22% w/w of a release retarding agent;

(c) about 2.5% to about 2.75% w/w of a binder, and

(d) about 0.75% to about 1.25% w/w of a lubricant.

66. The direct compression 750 mg niacin extended-release tablet formulation of claim 65 comprising:

(a) about 76% to about 79% w/w of niacin;

(b) about 17% to about 21% w/w of a release retarding agent;

(c) about 2.5% to about 2.7% w/w of a binder, and

(d) about 0.95% to about 1.05% w/w of a lubricant.

67. The direct compression 750 mg niacin extended-release tablet formulation of claim 66 further comprising a coating wherein said coating has from about 1.5 to about 8.0% weight gain.