HK1131888A - Low flush niacin formulation - Google Patents

Description

Low-flush niacin formulation

Technical Field

The present invention relates to a sustained release matrix formulation capable of being directly compressed into a tablet comprising niacin, a delayed release agent, and other excipients. The resulting tablets of the invention exhibit improved manufacturing characteristics, good release characteristics, and reduced duration, severity and incidence of skin flushing commonly associated with niacin treatment.

Background

Nicotinic acid (nicotinic acid, also known as 3-pyridinecarboxylic acid, formula C) is known₆H₅NO₂) Has benefits associated with the treatment of hypercholesterolemia because it increases the levels of High Density Lipoproteins (HDL), and decreases the levels of total serum cholesterol, Low Density Lipoproteins (LDL), and triglycerides.

Although niacin is known to provide a very beneficial effect on blood lipids, other than NIASPAN(Kos Pharmaceuticals, inc., Cranbury, NJ), in addition, the widespread use of niacin is limited by the high incidence of "flushing" that often occurs with higher doses of niacin required for effective lipid therapy. Flushing is a term commonly used to describe niacin-induced vasodilation. As a result, an individual experiencing flushing after niacin administration may develop a visible, uncomfortable sensation of fever or flushing. Although it is a mixture ofHowever, certain substances and/or formulations have been proposed to avoid or reduce skin flushing (see U.S. Pat. nos. 4,956,252, 5,023,245 and 5,126,145), but the deleterious side effects remain a problem with the widespread use of niacin products.

In addition, are commercially availableCurrent delayed release agents (also commonly referred to as "swelling agents") in formulations are highly variable in quality, thus resulting in the need for specialized mass production by manufacturers to meet intrinsic requirements.

Accordingly, there is a need for pharmaceutical technology for sustained release niacin formulations that provide reduced levels of skin flushing compared to existing niacin formulations, while also allowing for a stable manufacturing process characterized by improved physical, chemical and mechanical properties.

Summary of The Invention

The present invention provides a sustained release (ER) tablet comprising niacin and a delayed release agent. In one embodiment, the present invention provides 1000mg ER niacin tablets with improved flowability, compressibility, compactability, and hardness over existing 1000mg prescription niacin formulations. In addition, the 1000mg ER niacin tablet of the present invention demonstrates the ability to replicate the commercially available 500mg NIASPANThe release rate and/or absorption rate of the tablet without any reduction in manufacturing stability (a stable process is one that has the ability to replicate the target endpoint under varying environments or conditions, such as small variations in raw materials or manufacturing processes) or commercial needs (e.g., size). Because it is believed that 2 tablets of 500mg are usedThe tablet is characterized by being 1000mg than 1 tabletLess flushing of the tablet, it is therefore an object of the present invention to provide a bioequivalence of 2 tablets of 500mg1000mg ER Niacin tablet.

In particular, the present invention provides a pharmaceutical composition comprising:

(a) from about 70% to about 92% w/w niacin;

(b) about 7% to about 25% w/w of a delayed release agent;

(c) from about 0.1% to about 4.3% w/w binder, and

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

In one embodiment, the pharmaceutical tablet is a direct compression tablet.

Further, the present invention provides a method for preparing a sustained-release nicotinic acid tablet, comprising the steps of:

(a) blending a mixture of from about 70% to about 92% w/w niacin, from about 7% to about 25% w/w delayed-release agent, from about 0.1% to about 4.3% w/w binder, and from about 1.3% to about 4.3% w/w lubricant; and

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

In a preferred embodiment, the sustained release niacin tablet is prepared by blending granular niacin.

Also provided are methods of reducing flushing associated with niacin therapy in a patient, wherein the method comprises administering a sustained release niacin tablet according to the invention to a patient in need of niacin treatment. In a preferred embodiment, the niacin formulation according to the invention is administered during the evening or 1 time/day in the evening.

One embodiment of the present invention includes a 1000mg extended release niacin pharmaceutical composition that is reconstituted to compare a single dose of 4 tablets of 500mg when the composition is administered to a subject in a bioequivalence studyTablet and unit doseAn amount of said reconstituted 1000mg extended release niacin composition providing a 90% CI of the natural log conversion rate of suitable bioavailability parameters in the interval 80% -125%.

In accordance with the present invention, flushing may be further reduced by the administration of the extended release niacin formulation of the invention in combination with a non-steroidal anti-inflammatory drug (NSAID). In a preferred embodiment, the NSAID is aspirin.

Pharmaceutical compositions according to the present invention may comprise an immediate release flushing inhibitor component and a delayed release niacin component, wherein the niacin has a delayed release (i.e. niacin is released after a lag time). In a preferred embodiment, niacin is released at least about 30 minutes to about 40 minutes after the release of the flushing inhibitor.

Brief Description of Drawings

FIG. 1 shows a graph containing different levels of Methylcellulose (METHOCEL)Graph of the mean niacin dissolution rate of 1000mg niacin sustained release tablets of K-15M Premium.

FIG. 2 is a modification of methylcelluloseGraph of the effect of viscosity of K-15MP CR on niacin dissolution for a 1000mg niacin extended release tablet (1240mg total weight).

Figure 3 is a niacin dissolution profile for a 1000mg niacin sustained release tablet prepared using bulk and 40 mesh PVP K-90.

Figure 4 is a niacin dissolution profile for a 1000mg niacin extended release tablet (1240mg total weight) prepared using different mixing procedures.

FIG. 5 is a flow chart showing a direct compression manufacturing method.

FIG. 6 is a flow chart of the clinical study described in example 3.

FIG. 7 is a schematic view of a display deviceTo 2 film-coated 1000mg extended release niacin formulations of the invention (trial) and 2 uncoated 1000mgHistogram of the incidence of flushing after patch (reference).

FIG. 8 is a graph showing that 2 tablets of film-coated 1000mg extended release niacin formulation (trial) and 2 uncoated 1000mgAfter the slice (reference), a histogram of the median intensity of the first flushing event.

FIG. 9 is a graph showing the administration of 2 film-coated 1000mg extended release niacin formulations of the invention (trial) and 2 uncoated 1000mgAfter the patch (reference), histogram of median duration of first flush event.

FIG. 10 is a graph showing that 2 tablets of film-coated 1000mg extended release niacin formulation (trial) and 2 uncoated 1000mgAfter the tablet (reference), a histogram of the incidence of individual flushing symptoms in the first flushing event.

FIG. 11 is a graph of 2 tablets of 1000mg sustained release formulation ("tested" or "reconstituted") and 2 tablets of 1000mg of the present invention being administeredMean plasma concentration of niacin after the tablet ("reference").

FIG. 12 is a graph of 2 tablets of 1000mg sustained release formulation ("tested" or "reconstituted") and 2 tablets of 1000mgGraph of mean plasma concentration of NUA after a tablet ("reference").

FIG. 13 shows the administration of 2 of the present inventionA1000 mg sustained release formulation ("test" or "reconstituted") and 2 tablets of 1000mgHistogram of mean urine recovery of niacin and its metabolites (expressed as percent niacin dose) 96 hours after the tablet ("reference").

FIG. 14a is a graph of the linear mean plasma niacin profile for the 3 test extended release niacin formulations (ERN-1, ERN-2, ERN-3) and the reference extended release niacin formulation (NSP); figure 14b is a graph of the semi-log mean plasma niacin curve for the 3 test formulations and the 1 reference formulation.

FIG. 15a is a graph of the linear mean plasma NUA curves for the 3 experimental sustained release niacin formulations (ERN-1, ERN-2, ERN-3) and the reference sustained release niacin formulation (NSP); figure 15b is a graph of the median plasma NUA curves for the 3 test formulations and 1 reference formulation.

FIG. 16 is a bar graph showing the mean urinary recovery of niacin and its metabolites for the 3 test extended release niacin formulations (ERN-1, ERN-2, ERN-3) and the reference extended release niacin formulation (NSP) as a percentage of niacin dose.

FIG. 17a is a graph of the linear mean plasma niacin profile for 2 tablets of coated 1000mg extended release niacin formulation of the invention (test) and 2 tablets of uncoated 1000mg extended release niacin formulation of the invention ("reference"); figure 17b is a graph of log-transformed mean plasma niacin curves for the test formulation and the reference formulation.

FIG. 18a is a graph of the linear mean plasma NUA curves for 2 tablets of the coated 1000mg extended release niacin formulation of the invention (trial) and 2 tablets of the uncoated 1000mg extended release niacin formulation of the invention ("reference"); figure 18b is a graph of log-transformed mean plasma NUA curves for the test and reference formulations.

Figure 19 is a bar graph showing the mean urine recovery of niacin and its metabolites at 96 hours after administration of 2 tablets of the coated 1000mg extended release niacin formulation of the invention (trial) and 2 tablets of the uncoated 1000mg extended release niacin formulation of the invention ("reference").

FIG. 20 is a flow chart showing the study design of example 6.

FIG. 21 is a graph showing 2 tablets of a 1000mg extended release niacin formulation of the invention when (1) the subject was pre-treated with aspirin (ASA), (2) ASA was administered with the niacin formulation, and (3) the niacin formulation was administered aloneCF "), the incidence of individual flushing symptoms in the first flushing event.

Fig. 22 is a bar graph depicting the incidence of flushing events for example 3 and example 8.

Fig. 23 is a bar graph depicting the intensity of flushing events of examples 3 and 8.

Detailed description of the invention

The sustained-release matrix tablet of the present invention comprises (1) nicotinic acid as an active ingredient and (2) a hydrophilic polymer matrix, i.e., a delayed-release agent, which realizes sustained release of the active ingredient. As used herein, a "sustained release" formulation refers to a formulation that provides an effective treatment of dyslipidemia in a patient by 1/day administration.

The sustained release niacin formulation of the present invention may result in improved lipid profile in a patient. For example, administration of the extended release niacin formulation of the present invention to a patient can lower total cholesterol, Low Density Lipoproteins (LDL), triglycerides and lipoprotein a (lp (a)), and increase High Density Lipoproteins (HDL) in the patient's bloodstream. In need of treatment to lower total cholesterol, LDL, triglycerides and/or lipoprotein a (lp (a)); and/or a condition that increases HDL in the blood stream of a patient, referred to herein as "dyslipidemia". Accordingly, the present invention includes the treatment of dyslipidemia by administering the sustained release niacin formulation of the present invention to a patient in need of such treatment.

Bioequivalence is the activity in a pharmaceutical equivalent or a pharmaceutical alternative when administered at the same molar dose under similar conditions in a suitably designed studyThere is no significant difference in the rate and extent of availability of the ingredient or active moiety at the site of action of the drug. C, which typically demonstrates natural log transformation_maxAnd AUC or any suitable alternative of these calculated bioequivalence parameters, a 90% confidence interval for the trial/reference treatment ratio falling between 80% -125% (including 80% and 125%) is sufficient to conclude that the two formulations are bioequivalent.

Formulations within the scope of the present invention are those considered to be bioequivalent to the formulations of the present invention when 90% CI of the test/reference treatment ratio of the natural log transformed Bioavailability parameter falls within the standard 80% -125% interval (see, e.g., guidelines for Industry: bioavailablity and Bioequivalence Studies for organic Administered Drug products-General Considerations, u.s.department of Health & human services (u.s.department of Health and human services, industrial guidelines: General Considerations for Bioavailability and Bioequivalence Studies of oral drugs), Food and Drug Administration, CDER, 3 months 2003; guide for Industry-effort Bioavailability and flavor Studies; published in this publication in 12 dbs). As known to those of skill in the art, using relevant bioequivalence parameters, wherein a reference formulation is used as a control, such formulations are compared to reference formulations (e.g., those described herein or embodiments of the invention described herein) under the same analytical conditions (e.g., analytical and technical condition analysis).

Nicotinic acid

Nicotinic acid (water-soluble drug) is a white fine crystalline, granular or white crystalline powder commodity. The pharmaceutical compositions of the present invention may be prepared using niacin crystals, granules or powders. In a preferred embodiment, the pharmaceutical composition is prepared using a particulate niacin having greater flowability than the niacin powder. Flowability is a critical process parameter for tablet preparation. The use of particulate niacin to improve flowability in accordance with the present invention allows direct tableting of niacin tablets on a manufacturing scale. Any particle size of the particulate niacin is suitable for preparing the niacin tablets according to the invention. The preferred particle size of the niacin particles is: the particle size fraction NLT 85% (w/w) was sieved to make particles in the range of 100-425 μm, <100 μm dust NMT 10% (w/w). The use of dry granulation or wet granulation can enhance the flowability of the niacin powder.

Niacin will typically be present in the tablets of the present invention at a concentration of from about 70% to about 95% w/w, preferably from about 76% to about 90% w/w, more preferably from about 78% to about 82% w/w. Niacin may be present in the sustained release formulations of the present invention in amounts of about 100mg to about 3000 mg. In certain embodiments, the formulations of the present invention comprise about 500mg, about 750mg, or about 1000mg niacin. Preferred daily dosages of niacin are about 1000mg, about 1500mg, or about 2000 mg. Thus, for example, a daily dose of niacin may be provided to a patient by administering to the patient two 1000mg tablets 1 time per day.

Delayed release agent

Slow release from a polymer matrix system will typically include polymer wetting, polymer hydration, gel formation, swelling and polymer dissolution. With respect to soluble drugs, these drugs wet, dissolve and diffuse out of the gel layer formed by the polymer backbone. Although the release mechanism of soluble drug in matrix tablets depends on many variables, the general principle is that the water-soluble polymer (present throughout the tablet) hydrates at the outer surface of the tablet to form a gel layer. As water penetrates the tablet, the thickness of the gel layer increases and the soluble drug diffuses through the gel layer. The rate of drug release is determined by the diffusion of the soluble drug through the gel and by the rate of tablet erosion during the life of the ingested tablet.

The delayed release component of the present invention may be any agent known to those skilled in the art that demonstrates good swelling and gelling properties. Examples of suitable delayed release agents include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (also commonly referred to as HPMC or hypromellose), methylcelluloseCellulose (MC), hydroxyethyl cellulose (HEC) and polyvinylpyrrolidone (PVP), xanthan gum and copolymers of methacrylate with Trimethylammonioethylmethacrylate (TM) ((MC))) And mixtures of these delayed release agents. In one embodiment, the delayed release agent is a hydrophilic, water-soluble polymer. Preferred hydrophilic polymers are medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohol.

The delayed release agent will typically be present in the tablet of the present invention at a concentration of from about 7.0% to about 25.0% w/w (weight percent relative to the total weight of the formulation), preferably from about 11.0% to about 20.0% w/w, more preferably from about 14% to about 18% w/w.

In one embodiment, the delayed release agent is hydroxypropyl methylcellulose. HPMC has a polymeric backbone of cellulose (a natural carbohydrate containing the basic repeating structure of anhydroglucose units). The water solubility (e.g. hydration rate) and strength of the gel layer formed by HPMC is affected by the ratio of the two chemical substituents, i.e. hydroxypropoxy (sometimes called hydroxypropyl) and methoxy (sometimes called methyl) substitutions, attached to the cellulose backbone of HPMC (cellulose is a natural carbohydrate containing the basic repeating structure of anhydroglucose units). Hydroxypropoxyl substitution is relatively hydrophilic in nature and greatly contributes to the hydration rate, while methoxyl substitution is relatively hydrophobic in nature. The number of substituents on the anhydroglucose unit of cellulose can be specified by the average number of substituents attached to a single anhydroglucose ring, a concept commonly referred to as "degree of substitution" by those skilled in the art. SeeCellulose Ethers technical handbook, Dow Chemical Company (9.2002, publication No. 192. 01062. AMS 0902); and UsingCellulose ethers for controlled Release of Drugs in hydrophic Matrix Systems (published 7.2002, publication No. 198-. In one embodiment of the invention, the HPMC delayed release agent has a methoxy degree of substitution of from about 1.2 to about 2.0, a hydroxypropoxy molar substitution of from about 0.1 to about 0.3, preferably a methoxy degree of substitution of from about 1.4 to about 1.9, and a hydroxypropoxy molar substitution of from about 0.19 to about 0.24, more preferably a methoxy degree of substitution of from about 1.39 to about 1.41, and a hydroxypropoxy molar substitution of from about 0.20 to about 0.22, more preferably a methoxy degree of substitution of about 1.4, and a hydroxypropoxy molar substitution of about 0.21. Methyl celluloseK-15M (available from the Dow chemical Company, including specific K-15M subclasses such as K-15M premium and K-15M premium CR) is a preferred delayed release agent.

In addition, hydroxypropylmethylcellulose polymers of varying viscosity grades are commercially available. These include, for example, methyl cellulose with viscosity grades of 4000 and 15000mPas (1 centipoise (cps) ═ 1mPas (millipascal seconds))K, i.e. methylcelluloseK4M and methylcelluloseK15M from Dow Chemical Co, USA; and 4000, 15,000 and 39,000mPas viscosity grades of Metalose 90 SH from Shin Etsu Ltd, Japan. In an embodiment of the invention, the viscosity of the HPMC (measured at a 2% concentration in water at 20 ℃, e.g. ASTM D2363) is from about 11,000 to about 22,000mPas, preferably from about 13,000 to about 18,000 mPas.

To determine the specific characteristics required for a suitable polymer substitution that is not HPMC, one skilled in the art may vary the degree of substitution of the polymer (e.g., hydroxypropylcellulose) and may identify substitutions that match the dissolution profile of a formulation utilizing HPMC according to the invention (e.g., a formulation according to example 1 or 2).

Excipient

The tablets of the invention also comprise a binder. The binder can be any conventionally known pharmaceutically acceptable binder such as polyvinylpyrrolidone (also known as PVP, povidone, polyvinylpyrrolidone), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethacrylates, waxes, and the like. Mixtures of the above binders may also be used. In an embodiment of the invention, the binder comprises about 0.1% to 4.3% w/w, preferably about 0.2% to 3.25% w/w, more preferably about 2.5% to 3.0% w/w of the total weight of the tablet.

In addition, the tablet of the present invention contains a lubricant. Lubricants may be hydrophobic or hydrophilic and include those commonly known to those skilled 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. The addition of a lubricant to the formulation reduces friction between the die walls and the tablet during compression, aids in the flow of the powder (i.e., the flow of the mixed formulation into the hopper and die), and helps prevent sticking of the tablet material to the processing equipment. In one embodiment, the tablet of the invention comprises about 0.5% to 1.5% w/w 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.

Coating film

The sustained release tablets of the invention may also include coatings, as is known in the art of pharmaceutical solid dosage forms, to provide a colored coating, enhanced visual characteristics, to act as a moisture or odor barrier, to resist deterioration caused by environmental factors such as sunlight, temperature changes, or to mask the taste of the tablet. Such coatings may comprise polymers, plasticizers, and/or colored pigments, as known to those skilled in the art. Examples include OpadryAnd (4) coating. Any known method such as fluidized bed coater (for example) may be usedSuch as wurster coating) or pan coating systems, the coating is applied from a solution (e.g., an aqueous solution), solvent, or suspension. In one embodiment of the invention, the coating is a coloured coating, in particular opadryAnd (4) coating. In yet another embodiment, a colored coating is applied to the tablet in an amount of about 1.5 to about 8.0% weight gain, preferably about 1.75 to about 5.0% weight gain.

And 500mg tablet equivalent

A review of previous clinical studies showed: 2 tablets (2)1000mgTablets (1203.6 mg in tablet weight) and 4 tablets (4)500mgThe patch is not bioequivalent. Nicotinic acid 1000mgThe release ratio in the tablet is from 500mgThe release in the tablet is faster. Further studies confirmed 1000mg niacin ER tablets (tablet weight 1419.0mg) with 500mgThe double amount of ingredients in the tablet is not bioequivalent either. In the latter case, the dissolution rate of nicotinic acid in vitro from a 1000mg tablet is from 500mgThe tablets dissolved more slowly, while niacin absorbed more slowly in vivo from 1000mg niacin ER tablets than the reference (500 mg). Further studies showed that: reconstituted 1000mg niacin ER tablets with 1300.0mg and 1280.0mg tablet weights and 500mgTablets are also not bioequivalent due to their slower release rate.

For preparation, 500mg of 2 tabletsTablet bioequivalent 1000mg nicotinic acid ER tablets, the inventors prepared and tested various 1000mg nicotinic acid ER formulations in vitro to predict in vivo release and absorption characteristics. It is also based on the fact that: dissolution decreased with increasing polymer (delayed release) levels (w/w) in the tablets, and 1000mg of the test niacin ER tablets were reconstituted. Thus, the evaluation includes analysis of new ingredients (e.g., different types of polymers) and alternative manufacturing techniques (e.g., direct compression or roller compaction).

Table 1 illustrates various test formulations of 1000mg tablets having different total tablet weights.

TABLE 1

After initial evaluation of the various variables, the following 4 formulations were selected for further evaluation. At all time points, 500mg was used in 250ml simulated intestinal fluid at pH 1.2, 37 ℃ for 60 minutes, followed by pH6.8, 37 ℃ forAs a reference and using a USP type 3 apparatus, the following formulations were analyzed for variations based on dissolution profiles.

(i) Preparation of methyl fibers using Wet Granulation (WG) E10M

Nicotinic acid granules, methyl fibers, were weighed out according to the formulations specified for 1240mg, 1260mg, 1280mg and 1300mg formulationsE10M, povidone K90 and stearic acid, then granulated in a high shear granulator using deionized water as the granulating solution. Drying and grinding the wet granules, and then mixing with other granular methyl fibersE10M and stearic acid. The final well blended mixture was compressed into tablets using a BWI Manesty Beta tablet press (Thomas Eng, Hoffman Estate, IL) at a rate of 500 tablets/minute for a target tablet hardness of 16-18 Kp.

(ii) Preparation of methyl fibers using Direct Compression (DC) process E10M

Nicotinic acid granules and methyl fibers were weighed according to the recipe specified in Table 1E10M, povidone K90 and stearic acid, which were then added to an 8qt blender (LB-9322, petterson kelly, East Stroudsburg, PA) and blended for 10 minutes. The well blended mixture was compressed into tablets using a BWI Manesty Beta tablet press (thomas eng, Hoffman Estate, IL) at a rate of 500 tablets/minute for a target tablet hardness of 16-18 Kp.

(iii) Preparation of methyl fibers using WG Process K15M

Niacin USP, methyl fiber, was weighed according to the recipe specified in Table 1K15M and povidone K90, granulated in a high shear granulator using deionized water as the granulating solution. Drying and grinding the wet granules, and then mixing with other granular methyl fibersK15M and stearic acid. The final well blended mixture was compressed into tablets using a bwimerest Beta tablet press (Thomas Eng, Hoffman Estate, IL) at a rate of 500 tablets/minute for a target tablet hardness of 16-18 Kp.

(iv) Preparation of methyl fibers using DC Process K15M

Nicotinic acid granules and methyl fibers were weighed according to the recipe specified in Table 1K15M, povidone K90 and stearic acid, which were then added to an 8qt blender (LB-9322, petterson kelly, East Stroudsburg, PA) and blended for 10 minutes. The well blended mixture was compressed into tablets using a BWI Manesty Beta tablet press (thomas eng, Hoffman Estate, IL) at a rate of 500 tablets/minute for a target tablet hardness of 16-18 Kp.

Analyzing the changes including the processing tool; differences in polymer levels (see table 1); exchange of wet granulation, direct compression and rolling; difference in PVP levels; a change in tablet hardness; weight difference (+/-5%); reproducibility; difference in tabletting speed and tablet stability (release rate after storage, moisture absorption, etc.). The following 3 preparations achieved targeted drug release characteristics: (i) methyl fiberE-10M Wet granulation, (iii) methyl fiber(iii) K-15M Wet granulation and (iv) methyl fiberK15M direct compression method. After three months of stability studies, 3 formulations further showed good stability results.

Due to the economic and stability advantages identified in the above analysis, the use of methyl fiber was chosen for further analysisThe direct compression tablet of K-15M is a preferred embodiment. Thus, with respect to the reconstituted 1000mg niacin DC tablets, the effect on particle size was further evaluated; the particle size distribution of each component, the volume and bulk density of each component; different batches of each component; the content is uniform; hauser and Carr indices; fluidity; compressibility and friability. Table 2 summarizes the specific main materials used for the different experimental formulations. DMF is a drug administration file.

TABLE 2 materials for niacin ER1000mg DC tablet

Table 3 illustrates reformulated test 1000mg DC chips containing different excipient levels and associated physical properties. These formulations were prepared as described above with respect to the w/w% of the components set forth in Table 3.

TABLE 3

Fig. 1 provides an example comparison of dissolution profiles for the formulations described in table 3.

Table 4 depicts the comparison of various 1000mg experimental niacin formulations to 500mg in a clinical studyDissolution and bioavailability data of. The dissolution was calculated at 37 ℃ with 900mL of deionized water at 100rpm (basket method) using USP apparatus 1.

TABLE 4

The reproducibility of the reconstituted 1000mg niacin ER direct compressed tablet was investigated by varying the following parameters:

preparation parameters are as follows:

methyl fiberViscosity and hydroxypropoxyl content of K-15MP CR

Methyl fiberParticle size of K-15M

Particle size of nicotinic acid particles

Stearic acid content

Sieving of PVP K-90

Processing parameters are as follows:

mixing sequence and time

Hardness of tablet

Tablet speed

The data generated during the above reproducibility study are set forth in table 5 below and in figures 2-4.

Table 5: dissolution of Niacin Using USP apparatus 1 (detailed above), 1000mg Niacin ER tablets with varying size Niacin particles (1240mg)

Niacin granules	Batch number	1	3	6	9	12	20
									Niaspan 500	10.3	23	38.1	51.3	62.7	86.6
40-60 meshes		9.1	20.3	32.9	43.1	51.4	69.8
								60-80 mesh		10.1	21	33.2	43.4	52	70.6
80-100 mesh		10.5	21	32.8	42.6	51.1	70.1
								100-		11	22	34.2	44.4	53.2	72.3

Upon completing the analysis of the above variables, applicants found that there was no significant difference in niacin dissolution from the tablets prepared when the following variables were varied: methyl fiberViscosity and hydroxypropoxyl substitution of K-15M premium (CR), nicotinic acid granules of different particle sizes, PVP K-90 sieved through a 40 mesh sieve, stearic acid content 0.5% 2.0%, mixing step and mixing time. Larger particle size methyl fibersK-15M Premium (CR) and tablet hardness (especially below 8kp) increase the dissolution of niacin. Smaller size niacin particles and methyl fibersK-15MPremium CR showed higher compressibility. As the stearic acid content increases in the formulation, the push force decreases significantly. Higher tablet hardness is achieved with higher compression and tablet-pushing forces, which is required to achieve the target tablet hardness (18Kp) as the compression speed is increased.

In accordance with the above, the present invention includes a 1000mg niacin sustained-release (ER) tablet by wet granulation or direct compression, comprising:

(a) from about 70% to about 92% w/w niacin;

(b) from about 7% to about 25% w/w of a delayed release agent having a methoxy degree of substitution of from about 1.2 to about 2.0 and a hydroxypropoxy molar substitution of from about 0.1 to about 0.3;

(c) from about 0.1% to about 4.3% w/w binder, and

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

In a preferred embodiment, the formulation is prepared using a direct compression method.

The 1000mg slow-release nicotinic acid preparation and two 500mg slow-release nicotinic acid preparations are adoptedThe tablets are bioequivalent and would be expected to share the same potency and toxicity characteristics. Thus, administration of a 1000mg extended release niacin formulation of the invention may provide 500mg in two tabletsSimilar therapeutic benefits without causing treatment-limited hepatotoxicity or treatment-limited uric acid orThe glucose level increases to the point where it is necessary to discontinue use of the formulation of the invention. Toxicity problems associated with sustained release niacin formulations are well known to those skilled in the art. See, for example, "comparison of potency and toxicity of sustained release versus immediate release of niacin in hypercholesterolemic patients", McKenney et al, JAMA Vol 271, No. 9, 1994, 3/2; and "time release formulations of undenatured hepatotoxicity and niacin", Rader et al, The am. jour. of med., volume 92, month 1 1992, page 77.

Accordingly, one embodiment of the invention comprises administering a pharmaceutical composition of the invention to treat a patient in need thereof, wherein treatment reduces blood lipids without generally causing treatment limitations (i) hepatotoxicity and (ii) elevated uric acid levels or glucose levels, or both, followed by administering to the patient requiring such treatment to be discontinued when the composition is ingested by the patient 1 time/day. In yet another embodiment, the administration is performed during the night or 1 time/day in the evening (e.g., after a meal or before sleep).

Combination therapy

The 1/day niacin formulation of the present invention may be combined with an HMG-CoA reductase inhibitor. As used herein, "combination therapy" and "combination therapy" include the administration of the niacin formulation of the present invention and at least one additional active agent in the same or separate pharmaceutical dosage form. As used herein, combination therapy includes the simultaneous administration of the active agents and the sequential administration of the active agents as part of a treatment regimen.

Examples of HMG-CoA reductase inhibitors include, but are not limited to, lovastatin and related compounds disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds reported in U.S. Pat. Nos. 4,346,227 and 4,448,979, mevastatin and related compounds disclosed in U.S. Pat. No. 3,983,140, velostatin and simvastatin and related compounds discussed in U.S. Pat. Nos. 4,448,784 and 4,450,171, fluvastatin, atorvastatin, rivastatin and fluindostatin (Sandoz XU-62-320). Additional HMG-CoA reductase inhibitors include, but are not limited to, pyrazole analogs of the mevalonolactone derivatives disclosed in U.S. Pat. No. 4,613,610, indene analogs of the mevalonolactone derivatives disclosed in PCT application WO 86/03488, 6- [2- (substituted-pyrrol-1-yl) alkyl ] pyran-2-one and its derivatives disclosed in U.S. Pat. No. 4,647,576, SC45355 (3-substituted glutaric acid derivative) dichloroacetate of Searle, imidazole analogs of mevalonolactone disclosed in PCT application WO86/07054, 3-carboxy-2-hydroxy-propane-phosphoric acid derivatives disclosed in French patent No. 2,596,393, 2, 3-di-substituted pyrroles disclosed in European patent application No. 0221025A 14, Furan and thiophene derivatives, naphthyl analogs of mevalonolactone disclosed in U.S. patent No. 4,686,237, octahydro-naphthalene disclosed in U.S. patent No. 4,499,289, ketogenic organisms of lovastatin disclosed in european patent application No. 0142146a2, and other known HMG-CoA reductase inhibitors such as those disclosed in the following patents: british patent nos. 2,205,837 and 2,205,838; and U.S. patent No.

5,217,992；5,196,440；5,189,180；5,166,364；5,157,134；5,110,940；5,106,992；5,099,035；5,081,136；5,049,696；5,049,577；5,025,017；5,011,947；5,010,105；4,970,221；4,940,800；4,866,058；4,686,237.

Optionally, the pharmaceutical formulations of the present invention may also be administered in combination with other antilipidemic agents. Specific examples of antilipidemic drugs include, but are not limited to, bile acid sequestrants such as cholestyramine, colestipol, prochloraz (Secholex. RTM. and Polidexide. RTM.), probucol and related compounds disclosed in U.S. Pat. No. 3,674,836, lipoprotectane (Roner-Prang gram), Eisai E5050 (N-substituted ethanolamine derivatives), imatinib (HOE-402), orlistat (THL), isigmastanyl phosphocholine (SPC Roche), aminocyclodextrin (tanaseyoku), ajinomycin A J-814 (a glycocycoll derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanimid CL-277,082 and CL-283,546 (di-substituted urea derivatives), neomycin, para-aminosalicylic acid, aspirin, quaternary ammonium sulfate (polydamine) disclosed in U.S. Pat. No. 4,027,009, and polydiallyl ammonium chloride (polydiallyl chloride) derivatives disclosed in U.S. Pat. No. 4,759,923, Omega-3-fatty acids, fibric acid derivatives such as gemfibrozil, clofibrate, bezafibrate, fenofibrate, ciprofibrate and clinofibrate, found in different fish oil supplements, and other known serum cholesterol lowering drugs such as those described in the following patents: U.S. patent nos. 5,200,424; european patent application No. 0065835A1, European patent No. 164-.

The pharmaceutical formulations of the present invention may also be administered in combination with a flushing inhibitor. Flushing inhibitors include, but are not limited to, non-steroidal anti-inflammatory drugs such as aspirin and salicylate; propionic acids such as ibuprofen, flurbiprofen, fenoprofen, ketoprofen, naproxen sodium, carprofen, and suprofen; indoleacetic acid derivatives such as indomethacin, etodolac and sulindac; phenylacetic acids such as aclofenac, diclofenac, and fencloc acid; pyrrole acetic acids such as zomepirac and tolmetin; pyrazoles such as phenylbutazone and oxyphenbutazone; oxicams such as piroxicam; and anthranilic acids such as meclofenamic acid and mefenamic acid.

The flushing inhibitor may also be prostaglandin D₂Receptor antagonists including, but not limited to, the compounds disclosed in U.S. patent publication nos. 2004/0229844 and 2005/0154044. Preferred prostaglandins D₂The receptor antagonist is MK-0524 (Merck)& Co.)。

Sustained release

The present invention includes sustained release dosage forms. As used herein, "sustained release" means that little or no release occurs for a period of time (i.e., the lag time) after administration to a patient. The niacin formulation of the present invention may be provided in a sustained release dosage form as the only active agent in a pharmaceutical composition or as one of a plurality of active agents in a pharmaceutical dosage form (the other active agents may or may not be sustained release). Thus, for example, the pharmaceutical composition may comprise an immediate release flushing inhibitor component in combination with a slow release niacin component. For example, after administration of the pharmaceutical composition of the present invention to a patient, the immediate-release flushing inhibitor is released immediately and the delayed-release niacin component is released after a lag time (e.g., at least about 30 minutes to about 40 minutes).

Materials and methods well known in the art can be used to provide sustained release. These materials and methods include the following: a single unit capsule drug delivery system comprising an insoluble capsule containing a drug and a stopper. The stopper is removed after a predetermined lag time due to swelling, etching or dissolution. Pulse plugSystems (Scherer DDS, Ltd) are examples of such systems, wherein a balloon is closed at the open end with an inflated hydrogel plug. After contact with the dissolution medium or gastrointestinal fluids, the plug expands, pushing itself out of the capsule after a lag time. This is followed by a rapid drug release. The lag time can be controlled by manipulating the size and position of the plug. See, e.g., WO 90/09168; wilding et al, Pharm res.1992; 9: 654-657. The stopper material may be prepared from: insoluble, but permeable and swellable polymers (e.g. polymethacrylates) (see I，Bodmeier R，Pharm Res.1998；15(3)：474-481；I, Bodmeier R, Pharm Res.1999; 16(9): 1424-. The potential problem of variable gastric residence time can be overcome by an enteric coating system so that dissolution occurs only in the higher pH region of the small intestine. Saeger H, Virley P&Mac 226: a pulsatile release dosage form. Product letterFrom Scherer DDS, Ltd; 2004.

systems (Port Systems, LLC) are capsule Systems based on osmosis, consisting of a gelatin capsule coated with a semipermeable membrane (e.g., cellulose acetate) containing an insoluble plug (e.g., lipid) and an osmotically active agent and pharmaceutical agent formulation. Crison et al, proceded Intern Symp Control Rel Bioact mater.1995; 22: 278-279. After contact with the aqueous medium, the water diffuses across the semi-permeable membrane, causing an increase in internal pressure, ejecting the plug after a lag time. The lag time is controlled by the coating thickness.

For releasing the drug in liquid form, osmotically driven capsule systems may be used, wherein the liquid drug is absorbed into highly porous particles which release the drug through the orifice of a semipermeable capsule supported by expanding the permeable layer after dissolution of the barrier layer. See U.S. patent No. 5,318,558. The capsule system releases the drug by osmotic injection of water from the body. The capsule wall is constructed of an elastomeric material and has an aperture. As the permeation continues, the pressure within the capsule increases, causing the walls to stretch. The orifice is sufficiently small such that when the elastic wall relaxes, flow of the drug through the orifice substantially ceases, but when the elastic wall expands beyond a threshold, the orifice expands sufficiently to allow the drug to be released at a desired rate. Elastomers such as styrene-butadiene copolymers may be used. See U.S. patent No. 5,221,278; U.S. patent No. 5209746.

ClockSystem (West Pharmaceutical Services drug delivery)&Clinical Research Centre) is a solid dosage form coated with a lipid barrier comprising carnuba wax and beeswax together with a surfactant such as polyoxyethylene sorbitan monooleate. Wilding et al, Int J pharm.1994; 111: 99-102; niwa et al, J drug target.1995; 3: 83-89, the coating is in the same thickness as the filmThe emulsion is etched or emulsified in an aqueous environment for a proportional period of time and then dispersed with the core. In a study of human volunteers, it was shown that the lag time is independent of the residence time of the stomach, and that the presence of intestinal enzymes or the mechanical activity of the stomach or the gastrointestinal pH does not affect the redispersion of hydrophobic membranes. Gazzaniga et al, Int J pharm.1994; 2(108): 77-83. The lag time increases with increasing coating thickness.

Time varyingThe system is a core of a drug containing coated with hydrophilic swellable Hydroxypropylmethylcellulose (HPMC), the core being responsible for the lag phase before release. Gazzaniga et al, Eur JBiopharm.1994; 40(4): 246-250; gazzaniga et al, proceded Intern SympControl Rel Bioact mater.1995; 22: 242-243; EP 0572942. The use of an external gastro-resistant intestinal membrane overcomes the problems related to variations in the gastric emptying time. Sangalli et al, J ContrRel.2001; 73: 103-110. The lag time is controlled by the HPMC thickness and viscosity grade. The system is suitable for tablets and capsules. Conte et al, Drug Dev Ind pharm.1989; 15(14-16): 2583-2596.

The 2-active agent containing multilayer tablet may be formed from a 3-layer tablet construction comprising 2 active agent containing layers separated by a drug-free gellable polymer barrier layer. U.S. Pat. nos. 4,865,849; conte et al, Eur J pharm.1992; 38(6): 209-212;i, Bodmeier R, Int J pharm.1999; 187: 175-184. The 3 tablets were coated on 3 sides with impermeable ethylcellulose, without top coating. After contact with the dissolution medium, the dose incorporated into the top layer is rapidly released from the uncoated surface. The 2 nd dose was released from the substrate after etching and dissolution of the gelled barrier layer of HPMC. The gelling and/or dissolution rate of the barrier layer controls the occurrence of the 2 nd dose. The gelling polymer may comprise cellulose derivatives like HPMC, methylcellulose, or polyvinyl alcohols of different molecular weights, and a coating material comprising: ethyl cellulose, ethyl celluloseCellulose acid propionate, methacrylic acid polymers, copolymers of acrylic acid and methacrylic acid, and polyols.

Pulsatile systems with rupturable coatings rely on the disintegration of the coating to release the drug. The pressure required for rupture of the coating can be achieved by effervescent excipients, swelling agents or osmotic pressure. An effervescent mixture of citric acid and sodium bicarbonate can be incorporated into the tablet core coated with ethylcellulose. Carbon dioxide generated after water penetrates the core results in drug release after the coating is ruptured. Bussemer T, Bodmeier R, AAPS Pharm Sci.1999; 1(4 suppl): 434(1999). With increasing coating thickness and increasing tablet core hardness, the lag time increases.

High expansion agents (also known as superdisintegrants) can be used to design capsule-based systems comprising a drug, an expansion agent, and a rupturable polymer layer. U.S. patent No. 5,229,131. Examples of super disintegrants include cross-linked carboxymethyl cellulose, sodium starch glycolate and low-substituted hydroxypropyl cellulose. The swelling of these materials results in complete rupture of the membrane and subsequent release of the drug. The lag time is a function of the composition of the outer polymer layer. The presence of hydrophilic polymers such as HPMC reduces lag time. The system can be used for the delivery of solid and liquid pharmaceutical formulations.

Multiparticulate systems (e.g., beads or pellets in a capsule) can be used to provide delayed release of the 1 active agent and delayed release or other types (e.g., immediate) release of the 2 nd active agent. See, for example, U.S. patent No. 4,871,549.

Spatiotemporal drug delivery systems (Fujisawa Pharmaceutical co., Ltd.) are multiparticulate systems in which the drug is coated on a unique sucrose species followed by a swellable layer and an insoluble top layer. Ueda et al, J Drug targeting.1994; 2: 35-44; ueda et al, Chem PharmBull.1994; 42(2): 359-363; ueda et al, Chem Pharm Bull.1994; 42(2): 364-; hata et al, Int J pharm.1994; 110: 1-7. Bulking agents may include super disintegrants such as sodium carboxymethyl cellulose, sodium starch glycolate, L-hydroxypropyl cellulose, polymers such as polyvinyl acetate, polyacrylic acid, polyethylene glycol, and the like. Alternatively, an effervescent system containing a mixture of tartaric acid and sodium bicarbonate can be used. After water ingress, the swellable layer expands, causing the membrane to rupture, followed by rapid release of the drug. The release is independent of environmental factors such as pH and solubility of the drug. The lag time can be varied by varying the thickness of the coating or by adding a large amount of lipophilic plasticizer to the outermost layer. U.S. patent No. 5,508,040.

Permeability control systems are based on a combination of osmotic and swelling effects. The core comprises a drug, a low bulk density solid and/or liquid lipid material (e.g., mineral oil), and a disintegrant. The core is then coated with cellulose acetate. After immersion in an aqueous medium, the water penetrates the core to displace the lipid material. After the lipid material is eliminated, the internal pressure increases until a critical stress is reached, causing the coating to break. U.S. patent No. 5,229,131.

Another system is based on capsules or tablets consisting of a large number of pellets, consisting of 2 or more pellets or parts (i.e. a population). Schultz P, Kleinebudde P.J Contr Rel.1997; 47: 181-189. Each pellet has a core containing a therapeutic agent and a water-soluble osmotic agent. A water permeable, water insoluble polymeric film surrounds each core. Hydrophobic, water-insoluble agents that alter permeability, such as fatty acids, waxes, or fatty acid salts, are incorporated into the polymer film. The rates of water influx and drug efflux result in a thin film coating per population that is different from any other pellet coating in the dosage form. The osmotic agent dissolves in the water causing swelling of the pellets, thus regulating the rate of drug diffusion. The effect of each pellet population sequentially releasing its drug content provides a series of releases of drug from a single dosage form. The thickness of the coating between the pellets can be varied.

Osmotically active agents that have not been expanded may also be used to provide delayed release. Schultz et al, JContr Rel.1997; 47: 191-199; U.S. patent No. 5,260,069. The pellet core is composed of medicine and sodium chloride. The core is coated with a semipermeable cellulose acetate polymer. The polymer is selectively permeable to water and impermeable to the drug. The lag time increases with coating thickness and with an increase in the amount of talc or lipophilic plasticizer in the coating. Sodium chloride promotes rapid release of the drug. In the absence of sodium chloride, a sustained release can be obtained after a lag time due to a lower degree of core expansion leading to small cracks.

A core-containing system coated with an insoluble permeable membrane, the core being a core of drug and osmotically active agent (sodium chloride), may be used to provide delayed release. U.S. patent No. 5,260,068. The coating material, which includes different types of acrylate-methacrylate copolymers and magnesium stearate, reduces the water permeability of the membrane, thus allowing the use of thinner membranes. Thicker films are avoided because they cannot be completely broken. The use of ethylcellulose as a coating material may affect the lag time of the enteric polymer to achieve rupture after a predetermined time. Bodmeier et al, Pharm Res.1996; 13(1): 52-56.

The permeability and water uptake of acrylic polymers having quaternary ammonium groups can be influenced by the presence of different counter ions in the medium. Beckert et al, proceded Int' l Symp control Rel Bioact Mater 1999; 26: 533-534. Several release systems based on said ion exchange have been developed. For this purpose Eudragit RS 30D is a preferred polymer because it contains in the polymer side chain a positively polarised quaternary ammonium group which is accompanied by a negative hydrogen chloride counter ion. The ammonium groups are hydrophilic, facilitating the interaction of the polymer with water, thus altering its permeability and allowing water to penetrate the active core in a controlled manner. Can use EUDRAGIT(10% -40% weight gain) the pellets were coated in 4 different layer thicknesses. The lag time is related to the film thickness. The drug permeability of the EUDRAGIT film depends on the amount of sodium acetate in the pellet core. After a lag time, the interaction between the acetate and the polymer increases the permeability of the coating so that the entire active dose is released within a few minutes. Guox. affects the physicochemical and mechanical properties of drug release from coated dosage forms. A doctor thesis. The university of Texas at Austin; 1996.

the sigmoidal delivery system comprises a pellet core containing drug and succinic acid coated with an ammonium-methacrylate copolymer USP/NF B type coating. Narisawa et al, Pharm Res.1994; 11(1): 111-116. The lag time is controlled by the rate of water flow into the polymer film. The water dissolves the succinic acid and drug in the core. The acid solution in turn increases the permeability of the hydrated polymer membrane. In addition to succinic acid, acetic acid, glutaric acid, tartaric acid, malic acid or citric acid may be used. Increased permeability can be explained by improved hydration of the membrane, increasing the free volume. These findings are used to design a delivery system with a coating comprising an acid core. Narisawa et al, Pharm Res.1994; 11(1): 111-116; narisawa et al, J Contr Rel.1995; 33: 253-260. In vitro lag times correlate well with in vivo data when tested with beagle dogs. Narisawa et al, J Contr Rel.1995; 33: 253-260.

The present invention includes pharmaceutical compositions comprising the niacin formulation of the present invention in a sustained release form in combination with a flushing inhibitor. The extended release of niacin and flushing inhibitor may be provided in 1 dosage form or in separate dosage forms. Thus, for example, a pharmaceutical composition may comprise a solid dosage form having an outer (immediate release flushing inhibitor component) and an inner (delayed release niacin component). In a preferred embodiment, the flushing inhibitor is released from about 30 minutes to about 40 minutes prior to the release of niacin.

The following examples are intended to better illustrate, but not limit, various embodiments of the present invention.

Example 1

The following formulations were used in this example:

TABLE 6

When using methyl fibersK-15M Premium, methyl fiberThe particle size specification for K-15MPremium is preferably such that a minimum of 90% passes a 100 mesh U.S. Standard sieve. For methyl fiberK-15M Premium CR, preferably passes at least 99% through a 40 mesh U.S. Standard Sieve and at least 90% through a 100 mesh U.S. Standard Sieve.

For a 20kg batch, the deblocked (delumped) niacin particles and excipients were weighed according to the above recipe and then added to an 8 quart blender and blended for 10 minutes at 24 rpm. In particular, a 12 mesh (1.68mm) screen was selected for the methyl fibersK-15M and stearic acid, and a 16 mesh (1.19mm) screen selected to de-agglomerate (optionally screened, milled, or both) the niacin particles and povidone K-90. The resulting granular composition was directly tabletted at 30kN using a BWI Manesty Beta press with a 19mm long oval tool. For a target tablet hardness of 18kP, the tablet hardness (i.e., the compression strength of the tablet, as measured by standard compression testing methods known to those skilled in the art) was controlled to be in the range of 16kP (kilopounds) to 22kP using a standard tablet hardness tester. The stearic acid or povidone may optionally be screened using a mesh screen, e.g., a 40 mesh screen, and the mixing step (1 or 2) and mixing time (10, 15 or 20) may be varied in alternate embodiments.

By adding 2% by weightOrange 03B93199, coating the resulting compressed tablets. The coating conditions were as follows:

TABLE 7

Control/test characteristics	Batch characteristics
		Batch size	12,097 tablet
Initial core weight (mg)	1236.3mg
		Final coated tablet weight (mg)	1286.3mg
Model # of Vector Hi coater (Vector Corp., Marion, IA)	HC-48/60
		Equipment #	002852
Lance-bed spacing	6 1/2”
		Spray gun #	2
Nozzle size	1.2mm
		Atomizing air	150L/min
Air mode	75L/min
		Volume of compressed air	170CFM
Spraying speed of 60g/min	59-64g/min
		Pot rotating speed (10RPM)	10rpm
Inlet temperature TBD	67.9-72.2℃
		The exhaust temperature is 43 DEG C	42.0-44.8℃
Weight increment: 50mg of	51.1
		Time of spray (report)	87 minutes

By comparing niacin assay, niacin dissolution, tablet moisture and physical appearance of the coated tablets before and after the stability study, it was found that 1000mg of coated niacin direct compressed tablets were stable for three months at 40 ℃/75% Relative Humidity (RH) and 25 ℃/60% RH.

Fig. 5 shows a flow diagram of a direct compression manufacturing process for making tablets according to an embodiment of the present invention.

Unless otherwise indicated, a 1000mg niacin sustained release formulation of the invention as described in the following examples was prepared according to example 1.

Example 2

Extended release direct compression tablets (coated or uncoated) of 500mg and 750mg with the content concentrations described in tables 8 and 9 below may be prepared using the methods described herein.

Table 8: 500MG tablet

Table 9: 750MG tablets

For 500mg and 750mg tablets, the deblocked niacin particles and excipients were weighed according to the component concentrations described in tables 8 and 9, and then blended in a suitable blender or mixer for the appropriate time to thoroughly mix the components. The resulting granular composition may then be compressed directly into tablets using a suitable tablet press, such as the BWI Manesty Beta press described above, to form the desired tablet content of 500mg or 750 mg. The 500mg and 750mg tablets are optionally coated, as with a color coating known in the art.

Example 3

Coated sustained release 1000mg niacin direct compression matrix tablet and 1000mgComparison of incidence of flushing therebetween

Method

The study was a randomized, double-blind, double-dummy (double-dummy), single dose, placebo-controlled, three-way cross-hatch, flushing challenge study performed at a single center. Subjects also excluded the use of aspirin or NSAIDs during the study.

The study included healthy, non-smoking male volunteers aged 18-70 years with a Body Mass Index (BMI) of 22-31. Subjects were confirmed as healthy by a comprehensive physical examination, medical history, electrocardiogram and results from clinical laboratory tests performed at the screening visit or at the approved visit of phase 1 study. The following subjects were excluded: if they have an allergic or hypersensitivity reaction to niacin or a related derivative; substance abuse or dependence within the last 3 years; there is a history of migraine, diabetes, gallbladder disease, liver disease, severe hypertension or hypotension, cardiac abnormalities, renal disease or pharmacogenetic myopathy. The subjects were not allowed to take any prescription drugs for 21 days prior to study participation, or were not allowed to take any over-the-counter drugs, vitamins or herbs for 10 days.

The screening procedure was completed within 21 days prior to clinical admission to the phase 1 study (figure 6). For each of the three study periods, subjects remained isolated from about 7:00AM on day 1 until all study procedures were completed on day 2 AM (7:00AM-10:00 AM). The diet composition and start time were the same for each study period. During each phase of the study, subjects received a diet according to a specific diet that controls niacin and fat content. Concomitant medications, vitamins or herbs and/or nutritional supplements were not allowed during the study.

Study treatment

Figure 6 depicts the formulations administered during the three study periods. Test treatment 1000mg tablets coated with 2 films of the invention (see example 1) (test-reconstituted nicotinic acid ER tablets), while reference treatment 2 uncoated 1000mg commercially available nicotinic acid ER tablets (reference-). Control treatment 2 uncoated placebo tablets (control) were used. Since the study focused on the flushing reported by the subjects, complete blinding of the subjects and researchers was very important to identify the agents administered in the treatment. Blinding is achieved by several methods. In each active agent treatment, 2 film coated placebo tablets like the active tablet or uncoated placebo tablets were co-administered with the active tablet so that all subjects received 2 film coated and 2 uncoated tablets regardless of treatment. In addition, study drug was administered to the subject from an opaque dosing cup, covering the subject's eyes during study drug administration. The study included placebo-controlled treatment to correct for expected placebo-responsive flushing results.

At approximately 11:00PM on day 1 of each study period, single doses of study drug were administered in a staggered manner according to a randomization schedule. There was a minimum of 7 days of rest between treatment sessions. Investigators and site personnel were blinded to the treatment allocation protocol and prohibited any site personnel involved in treatment allocation preparation and/or administration from collecting or evaluating treatment-emergent adverse events.

After the low fat snack, each dose was taken with a 240mL water port. All snacks were consumed within 15 minutes prior to study drug administration. Another 1 tablet was taken immediately after or simultaneously with 1 tablet and each subject was informed that dosing was complete within no more than 1 minute. Chewing or biting agents are prohibited. If the subject requested to add water to swallow the tablet, an additional 120mL increment of water was provided. The mouth of each subject was examined after administration of the study dose to confirm the consumption of the dose.

Variation of flushing

The incipient flushing variable is the occurrence of a flushing event or episode reported by the subject. A flushing event or episode is described as 1 or more of the following concurrent flushing symptoms: redness, fever, tingling and itching. During each study period, subjects were prompted to assess the presence or absence of flushing symptoms on an hourly basis up to 8 hours after study drug administration. Subjects were prompted to record the onset and cessation times of flushing symptoms, and the intensity rating (severity) of each symptom was assessed by marking vertical lines on a horizontal 10 cm Visual Analog Scale (VAS), fixed from "none" (0) on the left to "intolerable" (100) on the right. Information is recorded in an electronic flushing diary.

The 2 nd flush variables included the number of flush episodes, total flush events, and intensity and duration of each symptom of flushing (redness, warmth, tingling, and itching). The overall intensity rating for the first flushing event or episode for each subject was defined as beginning at the onset time of the 1 st of 1 or more concurrent flushing symptoms that occurred during the study period. The end time of a flushing episode is defined as the last cessation of 1 or more concurrent flushing symptoms occurring to that episode, which also follows a asymptomatic period lasting a minimum of 30 minutes.

Statistical analysis

Determination of the amount of sample required for 144 subjects to use McNemar's test (nQuery)Version 5.0) demonstrated a statistically significant difference in incidence of flushing between treatments at 5% (α). To ensure that a sufficient number of subjects will complete the study and to provide evaluable data from at least two treatments, early-discontinued subjects were replaced.

Initial efficacy assessments (incidence of flushing) were compared between treatment groups using the paired ratio McNemar's test equation. The primary comparison was made between the test and reference formulations of niacin ER in subjects receiving at least 1 dose of study drug over at least 2 study periods. Comparisons between niacin and placebo were also made. Evaluation 2 was compared using McNemar's test (for absolute variables) or paired t-test. All comparisons were two-tailed and were performed at α ═ 0.05.

Results

A total of 156 subjects were enrolled in the study and received at least 1 dose of study drug. Their mean age was 33.5 years and their mean BMI was 26.2. A summary of subject demographics is provided below in table 10.

TABLE 10 Baseline subject demographics

BMI-body mass index

All 156 subjects received study drug in phase 1, 143 subjects (92%) received study drug in phase two, and 131 subjects (84%) received study drug in phase 3. A total of 130 subjects (83%) completed dosing in all phases 3.26 subjects (17%) prematurely discontinued the study: 8 (5%) withdrawal commitments, 3 (2%) missed visits, 2 (1%) with adverse events, 2 (1%) protocol violations, 1 (1%) with positive drug screening, and the remaining 10 (6%) withdrawn for "other" reasons. To ensure sufficient strength, 11 of the subjects who prematurely discontinued the study were replaced.

Flushing with hot flashes

As expected, a flushing challenge was achieved because the incidence of flushing in active agent treatment was about 4-fold higher than in control treatment. Table 11 describes the incidence, intensity and duration of first flush events in a predetermined treatment (ITT) population defined as subjects receiving at least 1 dose of study drug and completing at least 1 study session, but not including replaced subjects. The placebo response seen in this study is a typical placebo response in general.

TABLE 11 incidence, Overall intensity and duration of first flush events in ITT populations

The incidence and overall intensity and duration of the first flushing event of the trial (reconstituted niacin ER) versus the reference (commercial niacin ER) (reference) in subjects receiving at least 1 dose of study drug for at least 2 study periods: A) the incidence of the first flushing event (p ═ 0.0027); B) intensity of first flushing event based on VAS; median values describe values [ mean of 35.6. + -. 22.78(Min, Max: 0.0, 99.0) for the test, mean of 52.8. + -. 23.86(Min, Max: 0.0, 95.0) for the reference, p <0.001 ]; C) duration of first flushing event (min); the median described [ mean of the trials 130.3 ± 95.01(Min, Max: 9.0, 473.0) and mean of the reference 195.7 ± 136.32[ Min, Max: 5.0, 984.0], p <0.0001 ].

As shown in fig. 7, for initial efficacy evaluation, 118 (89%) subjects experienced flushing during treatment with the test formulation among subjects who received at least 1 dose of study drug for at least 2 study periods; during treatment with the reference formulation, 130 (98%) subjects experienced flushing. The difference was statistically significant with a p-value of 0.0027.

Fig. 8 and 9 depict the median of the intensity and duration of the first flushing event. The mean values of intensity and duration and their respective median comparisons indicate: the potential distribution of these data is asymmetric. Relative to the reference treatment, the test treatment resulted in a 42% reduction in the median flush intensity (a 33% reduction in the mean flush intensity) and a 43% reduction in the median flush duration (a 33% reduction in the mean flush duration). Paired t-test showed: both the mean intensity (p <0.0001) and mean duration (p <0.0001) of the first flushing events for the experimental treatments were statistically significant improved.

Each of the four flushing symptoms (redness, fever, tingling and itching) had a lower incidence than the reference formulation (fig. 10). Using the McNemar's test, the comparison of the two formulations was significantly different, with the test formulation being beneficial for each of the 4 individual flushing symptoms of the first flushing event. The redness tested was 71% versus 86% for the reference formulation (p ═ 0.0016); the heat generation rate of the test was 68% compared to 80% for the reference formulation (p ═ 0.0163); the tingling rate of the test was 47% compared to 62% for the reference formulation (p ═ 0.0039); the rate of itching tested was 48% compared to 65% for the reference formulation (p ═ 0.0015).

The data show that: the formulations of the present invention reduce the incidence, intensity (severity) and duration of flushing compared to commercially available formulations. In summary, even though this study was designed to provoke flushing by administering a single large (2000mg) dose to subjects treated with niacin for the first time, the incidence of flushing (89%) for the formulations of the present invention was greater than that of the commercial niacin ER formulation(98%) was statistically significantly reduced by 9%. Administration of the formulations of the invention in the flushing challenge study also resulted in a highly statistically significant reduction in flushing intensity and duration. Median flushing intensity and duration were reduced by 42% and 43%, respectively, compared to the commercial niacin ER treatment. And the duration of the first flushing event of the formulation of the present invention is shortened by more than 1 hour.

Example 4

The objective of this study was to determine that a 1000mg extended release niacin tablet of the invention (hereinafter referred to as a "reconstituted" tablet) (trial) compares to the commercial one when administered as a single dose of 2000mg1000mgBioequivalence (BE) of the patch (reference).

Design of research

The study was a randomized, single-center, open, single-dose, two-way crossover study in 44 healthy, non-smoking, male and female volunteer subjects aged 40-70 years (including 40 years, 70 years). The exit is not replaced. Each subject received both niacin formulations (test and reference) at the same single dose of 2000mg for two separate periods with a pause of at least 10 days between doses. The test article is a reconstituted 1000mg sustained release nicotinic acid tablet and the reference article (reference) is 1000mgAnd (3) slicing. The low-fat snack was started at about 22:00 (hrs) on day 1 of each period, after which each dose was taken with 240mL of water. During each phase of the study (5 days for phase 1 and 6 days for phase two), subjects remained in the study room and received the diet according to the diet provided by the sponsor. No other medications, vitamins, herbs or nutritional supplements were allowed during the study.

Serial blood samples were collected from 30min before dosing up to 24 hours after dosing at the following intervals: 30min (pre-dose), 1,2, 3, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16 and 24hrs (post-dose). Urine samples were collected from 24hrs before dosing up to 96hrs after dosing at the following intervals: -24 to-18, -18 to-12, -12 to-6 and-6 to 0hrs (pre-dose); 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72 and 72 to 96hrs (post-dose). Plasma was analyzed for niacin and nicotinuric acid (NUA). Analysis of urine for niacin and its metabolites: NUA, N-Methylnicotinamide (MNA) and 2-PY (N-methyl-2-pyridone-5-carboxamide).

Nicotinic acid is extensively metabolized and plasma concentrations show much higher variability than NUA (one of its major metabolites). Thus the maximum plasma concentration (C) of NUA was used_max) To determine the absorption of niacin. Such asNDA indicates that total urine recovery is a more accurate measure of the extent of absorption than AUC, since AUC is more sensitive to non-linear pharmacokinetics. The total amount of niacin excreted in the urine as niacin and its 3 metabolites NUA, MNA and 2PY was therefore used as a measure of the degree of niacin absorption. Thus the primary variable used to evaluate the bioequivalence of a NUA defined in a protocol is the C of the NUA_maxTotal urine recovery of niacin and three metabolites (NUA, MNA and 2 PY).

The test drug consisted of 2 reconstituted 1000mg sustained release tablets of the invention. The reference medicine consists of 2 tablets 1000mgAnd (4) sheet composition. The treatment interval is at least 10 days.

During each session, subjects began a meal at the same time each day when they were confined to the clinic. The diet remains the same for each period, requiring the entire meal to be consumed. Breakfast, lunch, dinner and evening snacks began at approximately 07:00, 12:00, 18:00 and 21:45, respectively. The actual meal or snack time for each subject is scheduled based on the actual administration time. Subjects were asked to drink a minimum of 720mL of water on day-1, 1440mL of water on day 1 through day 5, in addition to 240mL of water on day 1 given with study medication.

On day-1, dinner and evening snacks were consumed. Breakfast, lunch, dinner and evening snacks were consumed on days 1 through 5. On day 1 of each period, the evening snack was eaten within 15 minutes prior to dosing. On day 6 of the second phase, no diet was consumed as subjects left the clinic after completing all clinical procedures.

Evaluation of pharmacokinetics

a. Plasma collection and analysis

Serial blood samples (15 samples/treatment) were collected from 30min before dosing to 24hrs post-dosing in each phase. Each blood sample was collected in a 10mL conical tube (vacutainer) containing sodium heparin, and allowed to cool in ice cream and water bath for a minimum of 5min after collection. The sample was centrifuged at about 3000rpm for 15min at 4 ℃ to separate the plasma. Each plasma sample was divided into 2 aliquots (aliquot a and aliquot B) and transferred to two pre-cooled, appropriately labeled polypropylene tubes. The samples were then frozen at about-20 ℃.

The concentrations of nicotinic acid and NUA were analyzed by liquid chromatography-mass spectrometry (LC/MS/MS). Niacin and NUA concentrations were obtained from the same injection. The Lower Limit of Quantitation (LLQ) of niacin and NUA in plasma was 2 ng/ml. Quality control samples were evaluated with each analysis run.

b. Urine collection and analysis

Urine was collected at the following intervals: -24 to-18, -18 to-12, -12 to-6, -6 to 0hrs (before administration); and 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72, 72 to 96hrs post-dose (11 total acquisitions).

Urine is collected and transferred to a tightly sealed plastic container. During the collection interval, the collected urine is kept chilled or placed in an ice-water bath. The collection container is marked to identify the number of subjects and the initial, collection interval time and protocol numbers. Empty containers are weighed to approximately one-tenth of a gram (e.g., 100.1g), written on containers and recorded on a laboratory source file worksheet. At the end of each interval, the total weight of the container and collected urine was weighed to approximately one-tenth of the gram recorded. The weight of the urine is obtained by subtracting the weight of the empty container from the total weight of the container plus urine. In some cases, the volume of urine during a given collection interval exceeds the capacity of a single container; a second container is therefore required to obtain a complete urine collection. The start and end dates and times of each urine collection interval were also recorded. 2 aliquots (approximately 2.5mL each) of each collection interval were transferred to 2 appropriately labeled polypropylene tubes. If more than one container is necessary during a particular collection interval, the urine in the two containers is mixed together prior to taking an aliquot. Samples were frozen at about-20 ℃ for analysis.

Urine samples were analyzed by validated LC/MS/MS for concentrations of niacin, NUA, MNA, and 2-PY. Urinary niacin and NUA concentrations were obtained from the same injection, while MNA and 2-PY concentrations were also obtained from the same injection. The LLQ value of nicotinic acid in urine is 20ng/ml, and the LLQ value of NUA is 200 ng/ml. The LLQ values of MNA and 2PY were 500ng/ml and 2500ng/ml, respectively. Quality control samples were evaluated with each analytical run.

c. Plasma pharmacokinetic parameters and urine recovery

Data from the subject providing information sufficient to calculate PK parameters for at least one treatment is included in the PK analysis. Following the administration of each treatment, the following PK parameters were calculated for each subject:

·C_max: maximum concentration observed

·T_max: time to maximum concentration observed

·AUC_last: area under concentration-time curve from time 0 to last measurable (non-0) concentration by linear trapezoidal method

·AUC_inf: area under the plasma concentration-time curve from time 0 to infinity; calculated as AUC_lastAnd C_tSum of/λ, where C_tIs the last observed concentration, and λ is the terminal elimination rate constant obtained from the natural log concentration-time curve.

·T_1/2: an apparent terminal half-life; calculated as a ratio of 0.693/lambda.

From urine data for niacin and its metabolites (NUA, MNA and 2-PY), the following parameters were calculated:

·CumX_u: cumulative amounts of each metabolite recovered from urine 0-96 hours after administration.

H% Fe: fraction of each metabolite excreted in urine relative to niacin dose within 96 hours after baseline recovery and correction of molecular weight after dosing.

Total% Fe: the total fraction of 4 metabolites within 96 hours after administration.

The% Fe of each analyte in urine was calculated as:

concentrations below the limit of quantitative detection were treated as 0. For plasma analysis, the actual sample collection time was used to calculate PK parameters. The amount of niacin and its metabolites recovered in the urine was determined by multiplying each metabolite concentration by the volume of urine collected at each interval. The total amount recovered in urine every 24 hour interval after dosing was adjusted to baseline by subtracting the amount recovered at the 24 hour interval before dosing. If any post-dose measurement is less than baseline, the amount is zeroed. The molecular weights of nicotinic acid and its metabolites NUA, MNA and 2-PY are 123.1, 180.2, 137.1 and 153.1, respectively. The% Fe and Fe of the 4 urine analytes were calculated and assigned as total% Fe.

Bioavailability parameters were calculated using the WinNonlin linear mixed effect model/bioequivalence, version 5.0.1 (26/7/2005) (as described above).

Statistical analysis

Using for Windows^TMIs/are as followsThe system, version 8.2, performed a statistical analysis of the bioavailability parameters calculated above.

Plasma pharmacokinetic parameters (C) were calculated as treatment and time period_max、T_max、T_1/2、AUC_lastAnd AUC_inf) And its natural logarithm conversion value (divided by T)_maxAnd T_1/2Outer) and summary statistics (n, mean, standard error, median, minimum, maximum, CV%). Plasma concentrations of niacin and NUA were summarized by time and treatment.

In PK analysis of nicotinic acid and NUA, natural log-transformed C was assumed_maxAnd AUC_lastThe data of (a) follow a normal distribution and are independent between the two treatments. Data were fitted to ANOVA models with mixed effects using SAS procmatrix by using treatment, period and order as fixed effects and subjects within the order as random effects. Estimating C based on the model_maxAnd AUC_lastAnd its corresponding 90% confidence interval.

The mean recovery of niacin and its metabolites in urine was calculated and summarized by treatment and by interval time. The sum of the total CumX and the fractions within 96 hours after administration were calculated and summarized as treatments_uAnd% Fe.

When used for plasma PK analysis, 90% Confidence Intervals (CIs) for the test/reference mean ratio of total% Fe were calculated by fitting the same ANOVA model.

Demographic variables (age, gender, race, weight, height, and elbow width) of the subjects were summarized by gender. The mean, Standard Deviation (SD), median, minimum and maximum values of the continuous demographic variables were calculated.

Results

Table 12 summarizes the subject profiles. A total of 44 subjects were added to the study after they met the protocol content and exclusion criteria. All of these subjects received at least one dose of study drug, of which 41 completed the study. 44 subjects received study medication at stage 1 according to the randomized treatment allocation in the protocol; however, 41 subjects received study medication in stage II. A total of 3 subjects discontinued the study. Subjects 0012 and 0039 discontinued the study in phase two. Subject 0038 withdrawn commitment at stage ii. The number of subjects interrupting the study was within the previously allowed 10% withdrawal rate, and was not considered to affect the results or conclusions of the study.

TABLE 12 summary of subject profiles

Of the 44 enrolled subjects, 25 were male and 19 were female. The mean age was 54.5 years; the average body weight was 169.8 pounds; average height is 68.0 inches; and an average elbow width of 2.6 inches. 37 subjects were caucasians, 6 were blacks, and 1 was indian americans. Table 13 summarizes the detailed demographic information.

TABLE 13 summary of subject demographics

a. Bioequivalence evaluation

For urinalysis, urine weight was converted to volume using a specific gravity of 1 g/mL. This is based on prior useThe study was conducted in which the average specific gravity measured for 962 samples was 1.009g/mL and the maximum specific gravity measured for 962 samples was 1.025 g/mL.

Fig. 11 and 12 show the mean plasma concentration curves for niacin and NUA, respectively, as treated. Figure 13 shows the mean urine recovery data.

b. Plasma NUA and total amount excreted in urine

Table 14 shows two main variables (C of NUA)_maxAnd total urine recovery of niacin and 3 metabolites) and NUA AUC_lastMean (SD) and statistical results. The table gives the results of BE analysis with and without reference treatment for subjects 0001, 0003 and 0014 with emesis episodes after dosing.

Subject 0001 developed emesis 7 hours and 20 minutes after the second phase of reference administration. Subject 0003 reference substance administered in second phaseThereafter, there were two episodes of vomiting at 8 hours 34 minutes and at 9 hours 20 minutes, respectively. 0014 emesis occurred 11 hours and 20 minutes after the reference was given at stage 1. The time to onset of emesis was at least 7 hours and 20 minutes after dosing for all 3 subjects. T of NUA and nicotinic acid_maxAll within 6 hours after administration. Therefore, emesis is not believed to affect PK parameters in these subjects.

TABLE 14 summary of NUA plasma parameters and Total urine recovery

^aParameters for defining bioequivalence of nicotinic acid

^bRecovery of niacin, NUA, MNA and 2PY together

^cN＝42；^dN＝39

As shown in the above table, NUA C_maxIs outside the bioequivalence range of 80-125%, but 90% CI of the test/reference mean ratio of niacin and metabolites recovered from urine is within 80-125%. Results with and without Reference (REF) treatment were similar for subjects 0001, 0003 and 0014.

The terminal elimination rate was calculated for each subject as a treatment. Average NUAT for test and reference_1/2Mean NUA T of 3.16 and 3.47 hours, respectively_max5.55 and 5.80 hours, respectively, and average NUA AUC_inf12510.8 and 18980.8ng × hr/ml, respectively.

c. Niacin in blood plasma

Table 15 provides the mean PK parameters for plasma niacin and statistical analysis. The table gives the results of the BE analysis with and without reference treatment for subjects 0001, 0003 and 0014. Nicotinic acid C_maxAnd AUC_lastIs less than 100%. Due to the fact thatHigh variability, the corresponding 90% CI of this ratio being outside the interval 80-125%. For subjects 0001, 0003 and 0014, the results with and without reference treatment were similar.

TABLE 15 summary of Niacin plasma parameters

Mean niacin T for test and reference_1/25.46 and 4.42 hours, respectively, mean T_max5.56 and 5.55 hours, respectively, and average AUC_inf13987.8 and 35296.6ng × hr/mL, respectively.

d. Urine recovery for each analyte

The average urine recovery for each analyte is given in table 16.

TABLE 16 summary of urinary excretion of nicotinic acid and its metabolites

^aRecovery of nicotinic acid dose%

As shown in the table above, the highest average urine recovery was 2PY, followed by MNA, NUA and niacin.

e. Conclusion of bioequivalence evaluation

NUA C based on niacin and its metabolites (total% Fe)_maxAnd 90% CIs of the mean test/reference ratio of urine recovery, the bioequivalence was evaluated. 90% CIs of the test/reference mean ratio of total% Fe is in the requisite 80-125% BE range, but NUA C_maxIs outside the bioequivalence range of 90% CIs of the test/reference mean ratio of (a). Supportive assay results (including NUAAUC)_last) Also falls within 80-1 as 90% CI of the test/reference mean ratio ofOutside the 25% range. Therefore, when reacting withThe reconstituted 1000mg ER nicotinic acid tablets (test) showed lower absorption and comparable absorption when compared to 1000mg tablets (reference). The test treatment is not bioequivalent to the reference treatment.

Example 5

The study was designed to determine that 3 formulations of the 1000mg extended release nicotinic acid tablet of the invention (hereinafter referred to as "reconstituted" tablets) compare to the commercially available formulation after a single 2000mg niacin doseBioequivalence of 500mg tablet.

Design of research

The study was a randomized, single-center, open, single dose, 4-way crossover study in 44 healthy, non-smoking, male and female volunteer subjects aged 40-70 years (including 40 years, 70 years). The exit is not replaced. Each subject received the same dose of oral study drug 2000mg niacin on 4 separate occasions with a minimum 10 day rest period between doses. Each subject received 2 tablets of 1000mg ER niacin formulation (ERN-1, ERN-2, ERN-3) and 4 tablets of 500mgAnd (4) tablets.

Consumption of the low fat snack was started at about 2200 hours, after which each dose was taken with 300mL of water. The subjects received a diet during each treatment period according to the diet provided by the sponsor. No other medications, vitamins, herbs or nutritional supplements were allowed during the study. Blood samples were collected before dosing and at regular intervals up to 24 hours after dosing; urine samples were collected 24 hours before dosing and 96 hours after dosing. Plasma was analyzed for NUA and niacin. Urine was analyzed for nicotinic acid and its 3 major metabolites: NUA, MNA and 2 PY. Subjects were housed during the 5 day study period for each treatment.

Diets (breakfast, lunch, dinner and evening snack) were provided to control niacin content during each treatment period.

The reference treatment was made of highly active granules (niacin, povidone and hydroxypropylmethylcellulose [ HPMC)]) Composition of 500mg commercially available(NSP) formulation, the granules are blended sequentially with stearic acid and additional HPMC prior to tableting.

The experimental treatment was 1000mg prepared according to 3 different reformulations of Table 17 belowFormulations (ERN-1, ERN-2 and ERN-3).

TABLE 17

Nicotinic acid granules, methyl fibers, were weighed according to the formula specified in Table 17 aboveK15M, Povidone K90 and stearic acid, then added to an 8qt blender (LB-9322, Petterson Kelly, East Stroudsburg, Pa.) and blended for 10 min. The well blended mixture was compressed into tablets using a BWI Manesty Beta tablet press (Thomas Eng, Hoffman Estar, IL) at a rate of 500 tablets/minute, with a target tablet hardness of 16-18 Kp.

All diets and beverages were free of alcohol and xanthine. Because there is niacin in the normal diet, the study diet was controlled to maintain niacin intake of about 25 mg/day while limiting the subjects to the clinic. At about 2200, each dose was administered immediately after the low fat snack was consumed.

On all days during each period, subjects began a meal at the same time and were confined to the clinic. The diet was the same for each period and all the food was consumed for each meal. Breakfast, lunch, dinner and evening snacks began at about 0700, 1200, 1700 and 2145, respectively. The actual meal or snack time for each subject is predetermined for the actual administration time. Subjects were asked to drink a minimum of 720mL of water on the first 1 day and 1440mL of water on days 1,2, 3, 4, and 5 in addition to 300mL of water on day 1 given with study medication.

In the first 1 day, dinner and evening snacks were consumed. Breakfast, lunch, dinner and evening snacks were consumed on days 1,2, 3, 4 and 5. On day 1 of each period, the evening snack was consumed within 15 minutes. On day 6 of each session, no diet was consumed as subjects left the clinic after completing all clinical procedures.

Evaluation of pharmacokinetics

a. Plasma collection and analysis

In each phase, blood samples were collected within 30 minutes prior to administration (i.e., predose) and 1,2, 3, 4, 4.5, 5, 6, 7, 8,9, 10, 11, 12, 14, 16, and 24 hours after administration. Samples were taken at the test area and the subjects remained sitting up in a chair. Blood was collected in 7mL conical tubes containing heparin sodium and allowed to cool in ice sheet and water bath for at least 5 minutes after collection. The sample was centrifuged at about 3000rpm for 15 minutes at 4 ℃ to separate the plasma. The plasma fractions were transferred to 2 pre-cooled, pre-labeled polypropylene tubes. The samples were frozen at about-70 ℃ until analysis.

Bioanalysis of plasma niacin and NUA concentrations was performed by HPLC chromatograph with MS/MS detection. Concentrations of niacin and NUA were obtained from the same injection. The Lower Limit of Quantitation (LLQ) of niacin and NUA in plasma was 2 ng/mL. Quality control samples were evaluated with each analytical run.

b. Urine collection and analysis

Urine was collected at the following intervals: 24 to-18, -18 to-12, -12 to-6, -6 to 0 hours (i.e. before administration) and 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72 and 72 to 96 hours after administration (total of 11 acquisitions/treatments).

Urine is collected and transferred to a tightly sealed plastic container. During the collection interval, the collected urine is kept chilled or in an ice-water bath. The collection container is marked to identify the number of subjects and the initial, collection interval time and protocol numbers. The total weight of urine collected during each interval is recorded to be approximately one tenth of a gram (e.g., 100.1 g). The start and end dates and times of each urine collection interval were also recorded. 2 aliquots (approximately 2.5mL) of each collection interval were transferred to 2 appropriately labeled polypropylene tubes. Samples for analysis were labeled to identify Kos, protocol number, subject number, date, time between collection, date and time of study. Aliquots were frozen at about-20 ℃ for use. Another aliquot was used for specific gravity measurements at the clinic site.

Urine samples were analyzed for niacin, NUA, MNA, and 2-PY. Bioanalysis of urinary niacin, NUA, MNA and 2-PY concentrations was performed by HPLC chromatograph with MS/MS detection. Concentrations of niacin and NUA were obtained from the same injection. The LLQ value of nicotinic acid in urine is 20ng/ml, and the LLQ value of NUA is 200 ng/ml. The LLQ values of MNA and 2-PY were 500ng/ml and 2500ng/ml, respectively. Quality control samples were evaluated with each analytical run.

c. Plasma pharmacokinetic parameters and urine recovery

Data from the subject providing information sufficient to calculate a pharmacokinetic parameter for the at least one treatment is included in the pharmacokinetic analysis. Following the administration of each treatment, the following pharmacokinetic parameters were calculated for each subject:

from plasma niacin and NUA data:

·C_max: maximum plasma concentration observed

·T_max: time to maximum concentration observed

·AUC_0-last: by a linear trapezoidArea under plasma concentration-time Curve calculated from time 0 to the last measurable concentration

Additional PK parameters were also calculated from NUA data:

·AUC_0-inf: AUC calculated from time 0 to infinity_0-last+C_t/K_elArea under the plasma concentration-time curve of (1), wherein C_tIs the last observed quantifiable concentration and K_elIs the terminal elimination rate constant.

·T_1/2: calculated as 0.693/K_elThe terminal elimination half-life of (1).

Niacin, NUA, MNA and 2PY data from urine:

·CumX_u: the corresponding urine recovery (i.e., the amount of each analyte recovered in the urine) for each analyte.

Fe: the voiding fraction in urine was calculated as

Total% Fe: overall recovery of niacin, NUA, MNA and 2 PY.

Concentrations below LLQ were treated as 0 and the actual sample collection time was used for analysis. Various curves of plasma niacin and NUA concentrations were generated using WinNonlin professional network version, version 4.1. Use of WinNonlin 4.1 andexcel 2000 generated mean curves of plasma niacin and NUA concentrations and urine recovery data. Plasma pharmacokinetic parameters were determined from each curve by WinNonlin. Because of the small quantifiable niacin concentrations and the lack of a well-defined terminal phase in each plasma curve, the terminal phase slope and apparent half-life of the plasma niacin data were not calculated.

All urine pharmacokinetic parameters were determined using WinNonlin 4.1 and Excel 2000. Determining the amount of each analyte recovered in the urine by multiplying the analyte concentration by the volume of urine collected at each interval; the amount recovered in urine at the 24 hour interval post-dose was then corrected to baseline recovery by subtracting the amount found at the 24 hour interval prior to dosing.

The molecular weight of the analyte is: nicotinic acid, 123.1; NUA, 180.2; MNA, 137.1; 2PY, 153.1. The percent recoveries of each analyte were summed to calculate the total percent of dose recovered.

Statistical analysis

The application is suitable for Windows^TMIs/are as followsThe system, version 8.02 summarizes the demographics. Consecutive demographics are summarized by mean, Standard Deviation (SD), median, minimum and maximum.

Bioequivalence parameters were evaluated using natural log-transformed data using bioequivalence software loaded into WinNonlin 4.1. The model includes the order, subjects within the order, time periods, and treatments.

Bioequivalence was assessed by classical 90% Confidence Interval (CI) estimation of the ratio of the test to reference (ERN-1/NSP, ERN-2/NSP, ERN-3/NSP) by the least squares method, based on the natural-to-log transformed data. Treatment is considered bioequivalent if 90% CIs is within 80-125%. For bioequivalence determination, the parameter used was C of plasma NUA_maxAnd the total amount of niacin and metabolites excreted in the urine. Niacin plasma (C) was also measured_maxAnd AUC_0-last) And confidence intervals for each% Fe (niacin, NUA, MNA, 2PY) of urine data.

Results

44 healthy, non-smoking males and females aged 40-70 years, including 40 and 70 years, were enrolled in the study in compliance with protocol content and exclusion criteria. Subjects were selected based on the absence of tobacco use for at least 120 days prior to receiving the 1 st dose of study drug and the absence of any clinically significant findings from medical history, physical examination, Electrocardiogram (ECG), and clinical laboratory evaluations.

Of the 44 subjects added, 41 completed the study. 28 subjects were male, and 16 subjects were female. The average age was 51 years, the average weight was 171 pounds, and the average height was 68 inches. 36 subjects were caucasians, 6 were black, and 2 were spain. Table 18 below sets forth detailed demographic information.

TABLE 18 summary of subject demographics

a. Bioequivalence evaluation

Plasma and urine data for reference (NSP) treatment are provided for 43 subjects. Plasma and urine data for the ERN-1 and ERN-2 test treatments are provided for 42 subjects. Plasma and urine data for the ERN-3 test treatment are provided for 41 subjects. Nominal time was used for the average table, average curve, individual curves and concentration list. For PK analysis, the following rules were used:

for sampling times of 1-10 hours (including 1 hour and 10 hours):the actual time is for a deviation of 5 minutes or more. For deviations of less than 5 minutes, the nominal time will be used.

For sampling times greater than 10 hours:the actual time is for a deviation of 10 minutes or more. For deviations of less than 10 minutes, the nominal time will be used.

Summary statistics of plasma niacin and NUA pharmacokinetic parameters are shown in table 18A.

Table 18 a: plasma organisms and the likeEffect parameters and statistical summaries

Each treatment consisted of 2000mg niacin, with an N of 42 for ERN-I and ERN-2, 41 for ERN-3, and 43 for NSP. NSP is the reference treatment.

^a.Natural-log converted nicotinic acid and NUA C_maxAnd AUC_0-lastThe ratio of the least squares method of (1).

^b.Provided T_maxMedian value and range.

Mean plasma profiles of niacin and NUA are shown in figure 14 and 5 in figure 1.

b. Plasma data

Niacin in blood plasma

All subjects had values below LLQ prior to dosing. All subjects had measurable niacin concentrations 4.5-12 hours after dosing after each treatment.

Mean nicotinic acid C of ERN-1, ERN-2, ERN-3 and NSP_max5288, 4223, 5671 and 4707ng/ml, respectively. Mean niacin AUC for ERN-1, ERN-2, ERN-3 and NSP_0-last13896, 10207, 13507 and 12315ng hr/ml, respectively. Nicotinic acid T of ERN-1 and ERN-3_maxThe median was 6.0 hours and for ERN-2 and NSP was 5 hours.

Natural log transformed C of all three trial treatments_maxAnd AUC_0-lastThe ratio to NSP is greater than 100%. Nicotinic acid C of ERN-1, ERN-2 and ERN-3_maxThe ratios of (a) to (b) were 139%, 116% and 166%, respectively. Niacin AUC for ERN-1, ERN-2 and ERN-3_0-lastThe ratios of (a) to (b) are 137%, 112% and 151%, respectively. Natural log transformed nicotinic acid C of ERN-1, ERN-2 and ERN-3_maxThe 90% CIs are 113- & ltSUB & gt 170%, 94-142%, and 135- & ltSUB & gt 203%, respectively. To the natural logarithmConverted niacin AUC_0-lastThe 90% CIs for ERN-1, ERN-2 and ERN-3 are 114-. C_maxAnd AUC_0-lastThe 90% CIs are all outside the equivalence range of 80-125%.

High variation in nicotinic acid data, C for all 4 treatments_maxAnd AUC_0-lastThe CVs of (C) is in the range of 76-171%.

Uric acid of blood plasma cigarette

Three subjects had positive pre-dose NUA concentrations. They were subject 0028 (phase II, ERN-1, concentration 4.47ng/mL), subject 30 (phase II, ERN-3, concentration 2.75ng/mL) and subject 33 (phase II, ERN-2, concentration 3.26 ng/mL). Because the pre-dose concentrations of 0028, 0030, and 0033 in subjects were only about 0.24%, 0.06%, and 0.53% C, respectively_maxTherefore, no correction was made for these plasma curves. After each treatment, all subjects had measurable concentrations of NUA 3-16 hours post-dose.

Average NUA C of ERN-1, ERN-2, ERN-3 and NSP_max2822, 2616, 3058 and 2540ng/mL, respectively. Mean NUA AUC for ERN-1, ERN-2, ERN-3, and NSP_0-last13664, 12069, 13960, and 13070ng × hr/mL, respectively. NUAT for ERN-1 and ERN-3_maxThe median was 6.0 hours, 5.5 hours for ERN-2 and 5.0 hours for NSP.

The terminal elimination rate was calculated as much as possible for each subject and treatment. Average t of ERN-1, ERN-2 and ERN-3_1/2Respectively for 3.4hr and 3.1hr for NSP. Mean AUC of ERN-1, ERN-2, ERN-3 and NSP_inf13602, 11913, 14136 and 13009ng × hr/mL, respectively.

Natural log transformed C for ERN-1 and ERN-3 treatment_maxAnd AUC_0-lastThe ratio to NSP is greater than 100%. For ERN-2, C_maxRatio greater than 100% and AUC_0-lastThe ratio is less than 100%. NUA C of ERN-1, ERN-2 and ERN-3_maxThe ratios were 111%, 105%, and 123%, respectively. NUA AUC for ERN-1, ERN-2 and ERN-3_0-lastThe ratios are respectively 104%, 95% and 109%. Natural log transformed NUA C of ERN-1, ERN-2 and ERN-3_maxThe 90% Cls are respectively 121%, 96-115% and 135% for 101-. NUA AUC for natural log transform_0-lastThe 90% CIs for ERN-1, ERN-2 and ERN-3 were 96-111%, 88-102% and 102-118%, respectively. C of ERN-1 and ERN-2_maxAnd AUC_0-lastThe 90% CIs are all within the bioequivalence range of 80-125%. For ERN-3, C_max90% CI outside the 80-125% range but AUC_0-lastIs in the range of 80-125%.

High variation in NUA data, C for all 4 treatments_maxAnd AUC_0-lastCVs of (a) is about 48-58%.

c. Urinary recovery of niacin and metabolites

Urine weight is converted to volume using specific gravity 1. This is based on prior useThe study was conducted in which the average specific gravity measured for 962 samples was 1.009g/mL and the maximum specific gravity measured for 962 samples was 1.025 g/mL.

The mean urine recovery data is shown in table 19, depicted in fig. 16.

TABLE 19 summary of urine bioavailability parameters and statistics

Each treatment consisted of 2000mg niacin, with an N of 42 for ERN-1, ERN-2 and NSP and 41 for ERN-3.

NSP as a reference treatment

^aRatio of recovery and total recovery of niacin, NUA, MNA, 2PY of natural log transformation of least squares.

^bRecovery of niacin, NUA, MNA, and 2PY together.

^cBioequivalence was suggested (i.e. 90% CI of natural log transformed MNA, 2PY recovery and total recovery within 80-125%).

Overall recovery rate

Urine niacin total recovery as niacin, NUA, MNA and 2PY was 67.14% for NSP and 63.91%, 63.44% and 66.16% for ERN-1, ERN-2 and ERN-3, respectively. The least squares ratio of the overall recovery log-transformed% Fe for ERN-1, ERN-2 and ERN-3 were 95%, 94% and 98%, respectively. The 90% CI for the ratios of ERN-1, ERN-2 and ERN-3 were 91-99%, 90-98% and 94-102%, respectively, indicating that the total amount of excretion in urine was the same for the 3 test formulations as for NSP based on the 80-125% confidence interval.

d. Conclusion of bioequivalence evaluation

Pharmacokinetic analysis of NUA data showed: all 3 formulations tested (ERN-1, ERN-2, ERN-3) consist of C_maxThe peak exposure was measured to be 5-23% higher than the test formulation NSP. Logarithmic conversion of ERN-1 and ERN-2C_maxIs in the range of 80-125% for a least squares mean ratio of (c), indicating: these formulations are bioequivalent to NSP with respect to NUA. For ERN-3, C_max90% CI of is outside the 80-125% range, indicating: the preparation ERN-3 is not bioequivalent to NSP.

The average total amount of niacin and metabolites excreted in the urine was 63-66% for the 3 test formulations and 67% for the NSP. The lowest excretion fraction was the parent nicotinic acid, followed by NUA, MNA and 2PY (37.2-40.0%). The overall recovery of the test formulation was measured to be 2-6% lower than NSP. The 90% CI for the least squares mean ratio of the total recovery of the log-conversion was in the range of 80-125%, so that 3 test formulations were equivalent compared to NSP.

Thus, one embodiment of the present invention includes a 1000mg extended release niacin pharmaceutical composition that is reconstituted in a single dose of 4 tablets of 500mg when administered to a subject in a bioequivalence studyThe 90% CI of the ratio of the natural log-transformed to provide the appropriate bioavailability parameter is in the 80% -125% interval compared to a single dose of the reconstituted 1000mg extended release niacin composition.

In a preferred embodiment, the bioavailability parameter is NUA C_max(ng/ml) and total recovery, or niacin C_max(ng/ml) and niacin AUC.

Example 6

The objective of this study was to determine the Bioequivalence (BE) of the coated and uncoated 1000mg sustained release nicotinic acid tablets (hereinafter "reconstituted" tablets) of the present invention when administered in a single dose of 2000 mg.

Design of research

The study was a randomized, single-center, open, single-dose, two-way crossover study in 44 healthy, non-smoking, male and female volunteer subjects aged 40-70 years (including 40 years, 70 years). The exit is not replaced. Each subject received both niacin formulations (test and reference) at the same single dose of 2000mg for two separate periods with a 10 day rest period between doses. The test article consisted of 2 coated reconstituted 1000mg sustained release nicotinic acid tablets and REF consisted of 2 uncoated reconstituted 1000mg sustained release nicotinic acid tablets. The low-fat snack was started at about 22:00 (hrs) on day 1 of each period, after which each dose was taken with 240mL of water. Subjects remained in the study site during the 6 day study period (first 1 day-5 days) of each treatment, during which the diet was received according to the diet provided by the sponsor. No other medications, vitamins, herbs or nutritional supplements were allowed during the study.

Serial blood samples were collected from 30min before dosing up to 24 hours after dosing at the following intervals: 30min (pre-dose), 1,2, 3, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16 and 24hrs (post-dose). Urine was collected from 24hrs before dosing up to 96hrs after dosing at the following intervals: -24 to-18, -18 to-12, -12 to-6 and-6 to 0hrs (pre-dose); 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72 and 72 to 96hrs (post-dose). Plasma was analyzed for niacin and NUA. Analysis of urine for niacin and its metabolites: NUA, MNA and 2-PY.

During each session, subjects began a meal at the same time each day when they were confined to the clinic. The diet remains the same for each period, requiring the entire meal to be consumed. Breakfast, lunch, dinner and evening snacks began at approximately 07:00, 12:00, 17:00 and 21:45, respectively. The actual meal or snack time for each subject is predetermined for the actual administration time. Subjects were asked to drink a minimum of 720mL of water on the first 1 day, 1440mL of water on day 1 through day 5, in addition to 240mL of water on day 1 given with study medication.

In the first 1 day, dinner and evening snacks were consumed. Breakfast, lunch, dinner and evening snacks were consumed on days 1 through 5. On day 1 of each period, the evening snack was eaten within 15 minutes prior to dosing. On day 6 of the second phase, no diet was consumed as subjects left the clinic after completing all clinical procedures.

Evaluation of pharmacokinetics

a. Plasma collection and analysis

Serial blood samples (15 samples/treatment) were collected from 30min before dosing to 24hrs post-dosing in each phase. Each blood sample was collected into 117 mL conical tube containing sodium heparin, and allowed to cool in ice cream and water bath for a minimum of 5min after collection. The sample was centrifuged at 4 ℃ for 15min at about 3000rpm to separate the plasma. Each plasma sample was divided into 2 aliquots (aliquot a and aliquot B) and transferred into two pre-cooled, appropriately labeled polypropylene tubes. The samples were then frozen at about-20 ℃ until analysis.

Nicotinic acid and NUA concentrations were analyzed by a validated liquid chromatography mass spectrometer (LC/MS). Niacin and NUA concentrations were obtained from the same injection. The Lower Limit of Quantitation (LLQ) of niacin and NUA in plasma was 2 ng/ml. Quality control samples were evaluated with each analytical run.

b. Urine collection and analysis

Urine was collected at the following intervals: -24 to-18, -18 to-12, -12 to-6, -6 to 0hrs (before administration); and 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72, 72 to 96hrs post-dose (11 total acquisitions).

Urine is collected and transferred to a tightly sealed plastic container. During the collection interval, the collected urine is kept chilled or placed in an ice-water bath. The collection container is marked to identify the number of subjects and the initial, collection interval time and protocol numbers. Empty containers are weighed to approximately one-tenth of a gram (e.g., 100.1g), written on the container and recorded on a source file worksheet in the laboratory. At the end of each interval, the total weight of the container and collected urine was weighed to approximately one-tenth of a gram and recorded. The weight of the urine is obtained by subtracting the weight of the empty container from the total weight of the container plus urine. In some cases, the volume of urine exceeds the capacity of a single container during a given acquisition interval; a second container is therefore required to obtain a complete urine collection. The start and end dates and times of each urine collection interval were also recorded. 2 aliquots (approximately 2.5mL each) of each collection interval were transferred to 2 appropriately labeled polypropylene tubes. If more than one container is necessary during a particular collection interval, the urine in the two containers is mixed together prior to taking an aliquot. The samples were frozen at about-20 ℃ until analysis.

Urine samples were analyzed by validated LC/MS/MS for concentrations of niacin, NUA, MNA, and 2-PY. Urinary niacin and NUA concentrations were obtained from the same injection, while MNA and 2-PY concentrations were obtained from the same injection. Niacin in urine has an LLQ of 20ng/ml, while NUA has an LLQ of 200 ng/ml. The LLQ values of MNA and 2PY were 500ng/ml and 2500ng/ml, respectively. Quality control samples were evaluated with each analytical run.

c. Plasma pharmacokinetic parameters and urine recovery

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

·C_max: maximum concentration observed

·T_max: time to maximum concentration observed

·AUC_last: area under concentration-time curve from time 0 to last measurable (non-zero) concentration by linear trapezoidal method

·AUC_inf: area under the plasma concentration-time curve from time 0 to infinity; calculated as AUC_lastAnd C_t/λ_zIn which C is_tIs the last observed concentration and lambda_zIs the terminal elimination rate constant obtained from the natural log concentration-time curve.

·T_1/2: an apparent terminal half-life; calculated as 0.693/lambda_zThe ratio of (a) to (b).

From urine data for niacin and its metabolites (NUA, MNA, and 2-PY), the following parameters were calculated:

·CumX_u: cumulative amounts of each metabolite recovered from urine at 0-96hrs post-dose.

H% Fe: fraction of each metabolite excreted in urine relative to niacin dose within 96hrs post-dose, after baseline recovery and correction of molecular weight.

Total% Fe: total fraction of 4 metabolites within 96hrs post-dose.

The% Fe of each analyte in urine was calculated as:

concentrations below the limit of quantitative detection were treated as 0. The amount of niacin and its metabolites recovered in the urine was determined by multiplying each metabolite concentration by the volume of urine collected at each interval. The total amount recovered in urine every 24 hour interval after dosing was adjusted to baseline by subtracting the amount recovered in the 24 hour interval before dosing. If any post-dose measurement is less than baseline, the amount is zeroed. The molecular weights of nicotinic acid and its metabolites NUA, MNA and 2-PY are 123.1, 180.2, 137.1 and 153.1, respectively. The% Fe and Fe of the 4 urine analytes were calculated and assigned as total% Fe.

Bioavailability parameters were calculated using the WinNonlin linear mixed effect model/bioequivalence, version 5.0.1 (26/7/2005) (as described above).

Statistical analysis

The application is suitable for Windows^TMFor data analysisThe system, version 8.2, performed a statistical analysis of the bioavailability parameters calculated above.

Plasma pharmacokinetic parameters (C) were calculated as treatment and time period_max、T_max、T_1/2、AUC_lastAnd AUC_inf) And its natural logarithm conversion value (divided by T)_maxAnd T_1/2Outer) and summary statistics (n, mean, standard error, median, minimum, maximum, CV%). Plasma concentrations of niacin and NUA were summarized by time and treatment.

For PK analysis of nicotinic acid and NUA, natural log-transformed C was assumed_maxAnd AUC_lastThe data of (A) follow a normal distribution and are unique between the two treatmentsStanding. Data were fitted to ANOVA models with mixed effects using SAS procmatrix by using treatment, period and order as fixed effects and subjects within the order as random effects. Estimating C based on the model_maxAnd AUC_lastAnd its corresponding 90% confidence interval.

The mean recovery of niacin and its metabolites in urine was calculated and summarized by treatment and by interval time. The sum of the total CumX and the fractions within 96hrs after administration were calculated and summarized as treatments_uAnd% Fe.

When used for plasma PK analysis, 90% Confidence Intervals (CIs) for the test/reference mean ratio of total% Fe were calculated by fitting the same ANOVA model.

Demographic variables (age, gender, race, weight, height, frame size, elbow width, and BMI) of the subjects were summarized by gender. The mean, Standard Deviation (SD), median, minimum and maximum values of the continuous demographic variables were calculated.

Results

Table 20 summarizes the subject profiles. A total of 44 subjects were added to the study after they met the protocol content and exclusion criteria. All of these subjects received at least one dose of study drug, of which 42 completed the study. 44 subjects received study medication at stage 1 according to the randomized treatment allocation in the protocol; however, 42 subjects received study medication in phase II. A total of 2 subjects discontinued the study. The number of subjects interrupting the study was within the previously allowed 10% withdrawal rate, and was not considered to affect the results or conclusions of the study.

TABLE 20 summary of subject profiles

Of the 44 subjects added, 20 were male and 24 were female. The mean age was 53.1 years; the average body weight was 161.5 pounds; average height is 65.6 inches; the average elbow width was 2.7 inches; the average BMI was 26.3kg/m². The frame sizes are graded as small, medium, and large. 9 subjects had small frame sizes, 20 subjects had medium frame sizes and 15 subjects had large frame sizes. 38 subjects were Spanish, 4 caucasian, and 2 black. Table 21 summarizes the detailed demographic information.

TABLE 21 summary of subject demographics

a.Bioequivalence evaluation

Data from 42 subjects treated with the trial and 44 subjects treated with REF were analyzed to determine bioequivalence. The actual time relative to the time of administration was used in all analyses.

For urinalysis, urine weight was converted to volume using a specific gravity of 1 g/mL. This is based on prior useThe study was conducted in which the average specific gravity measured for 962 samples was 1.009g/mL and the maximum specific gravity measured for 962 samples was 1.025 g/mL.

Fig. 17 and 18 show curves of mean plasma concentrations of niacin and NUA, respectively, as treatments. Figure 19 shows the mean urine recovery data.

b.Plasma NUA and total amount excreted in urine

Defining the main variable for assessing bioequivalence of nicotinic acid as C of NUA_maxAnd total urine recovery of niacin and three metabolites (NUA, MNA and 2 PY).

Table 22 gives the mean (SD) and statistics of these 2 variables. Table 22 also shows the NUA AUC_lastMean (SD) and statistical analysis.

Table 22: summary of NUA plasma parameters and total urine recovery

^aParameters for defining bioequivalence of nicotinic acid

^bRecovery of niacin, NUA, MNA and 2PY together

^cSupport data for bioequivalence

As shown in the above table, the primary BE variable NUA C_maxAnd the 90% CI of the natural log transformed test/reference ratio for the total recovery of niacin and metabolites was within 80-25%. NUA AUC of natural log transform_lastAlso within 80-125% of the test/reference ratio.

The terminal elimination rate was calculated for each subject as a treatment. Average NUAT for test and reference_1/23.16 and 3.04hrs, respectively, mean NUA T_max4.90 and 4.80hrs, respectively, and average NUA AUC_inf10914.7 and 11770.6ng × hr/ml, respectively.

c.Niacin in blood plasma

Table 23 gives the mean PK parameters for plasma niacin and statistical analysis. Nicotinic acid C of natural logarithm conversion_maxAnd AUC_lastIs less than 100%. Due to high variability, fromLog transformed nicotinic acid C_maxAnd AUC_last90% CI of the ratio of (A) is outside the interval 80-125%.

Table 23: summary of nicotinic acid plasma parameters

Test and REF mean Niacin T_1/24.73 and 2.94hrs, respectively, mean T_max4.68 and 4.64hrs, respectively, and average AUC_inf11553.1 and 16134.3ng × hr/ml, respectively.

d. Urine recovery for each analyte

The average urine recovery for each analyte is given in table 24.

Table 24: summary of urinary excretion of nicotinic acid and its metabolites

The highest mean urine recovery was 2PY, followed by MNA, NUA and niacin.

e. Conclusion of bioequivalence evaluation

Based on NUA C_maxAnd 90% CIs of the mean test/reference ratio of urine recovery (total% Fe) of niacin and its metabolites, the bioequivalence was evaluated. Ratio of natural log-transformed niacin absorption (NUA C)_max) And the 90% CIs to the test/reference mean ratio of extent (total% Fe in urine) is in the range of 80-125% of the required BE, indicating: the test formulation is bioequivalent to the REF formulation. NUA AUC_lastThe 90% CI was also in the 80-125% range, supporting the BE conclusion.

For nicotinic acid C_maxAnd AUC_lastNicotinic acid C_maxAnd AUC_lastThe upper limit of 90% CIs of the test/reference mean ratio of (a) falls within the bioequivalence range, while the lower limit is very close to the lower limit of 80% of the bioequivalence range.

Example 7

For the 1000mg formulations of the invention analyzed in examples 4, 5, and 6, the NUA C is set forth in Table 25 below (except ERN-3)_max(ng/ml), Total urine recovery (%), Niacin C_max(ng/ml) and mean of niacin AUC.

Table 25: average bioequivalence of 1000mg formulation of the invention

^*() Standard deviation of

Thus, one embodiment of the present invention comprises a 1000mg extended release niacin pharmaceutical composition that, when administered to a patient in need thereof as a single 2-tablet 1000mg tablet, provides the following in vivo plasma profile: 90% CI of the ratio of natural log-transformed of at least one of the following bioavailability parameters is within 80% -125%:

(a)2601.8ng/mL NUA C_max；

(b) Total recovery of urinary niacin of 60.5%;

(c)4958.9ng/mL niacin C_max(ii) a And

(d) niacin AUC of 12414.5 ng/mL.

Table 25a below sets forth the upper and lower limits of the bioavailability parameters selected in table 25, taking into account standard error (shown in parentheses). In particular, the lower limit is calculated by the following method: from examples 4, 5 and 6 above, for each parameter identified in table 25 above, the lowest mean was identified, and 2 standard errors were then subtracted from that mean to yield the lower limit. The standard error is calculated by dividing the standard deviation by the square root of the sample size (e.g., 1430/√ 44 ═ 326). Likewise, the upper limit represents the highest mean value of each parameter from examples 4, 5 and 6 plus 2 standard errors.

Table 25 a: upper and lower limits of selected bioavailability parameters

Parameter(s)	Lower limit (Standard error)	Upper limit (standard error)
			NUA Cmax(ng/ml)	2111.0(326)	3253(431)
Total recovery (%)	49.24(4.4)	70.23(2.53)
			Nicotinic acid Cmax(ng/ml)	3096(1126)	6750(1462)
Nicotinic acid AUC	6723(3484)	18643(4747)

Thus, a further embodiment of the invention comprises a 1000mg extended release niacin pharmaceutical composition which, when administered to a patient in need thereof as a single 2-tablet 1000mg tablet, provides the following in vivo plasma profile: 90% CI of the ratio of natural log-transformed of at least one of the following bioavailability parameters is in the interval 80% -125%:

(a) NUA C of about 2111.0ng/mL to about 3253ng/mL_max；

(b) A total urinary niacin recovery of about 49.24% to about 70.23%;

(c) nicotinic acid C from about 3096ng/mL to about 6750ng/mL_max(ii) a And

(d) niacin AUC of about 6723ng/mL to about 18643 ng/mL.

Example 8

Comparison of incidence of flushing induced by extended release niacin at 2000mg dose when pre-treated with aspirin or co-administered with aspirin

This study was a single-center, randomized, double-blind, double-dumb, single-dose, three-way crossover study designed to study the effect of aspirin pretreatment and aspirin co-administration on the flushing response caused by oral administration of the sustained release niacin tablets of the invention. The design and treatment of the study is shown in figure 20. At any time during the study, subjects also avoided the use of non-study related aspirin or other NSAIDS. The study was approved by the clinical institutional review board, and each subject provided a written interview volunteer book prior to participation.

The study included ages 19 to 70 years with 22-31kg/m²Healthy adult males of Body Mass Index (BMI). Women were excluded from this study to avoid confusion between niacin-induced flushing events and perimenopausal flushing. Subjects were confirmed as healthy by a comprehensive physical examination, medical history, electrocardiogram and results from clinical laboratory tests performed at the screening visit or at the approved visit of the first phase study. The following subjects were excluded: provided they used any tobacco or nicotine product within 4 months of participation in the study; allergic or hypersensitivity reactions to niacin, aspirin, or related derivatives; substance abuse or dependence within the last 3 years; or a history of migraine, diabetes, gallbladder disease, liver disease, severe hypertension or hypotension, cardiac abnormalities, renal disease, or pharmacogenetic muscle. Subjects avoided any prescription drug for 21 days prior to participation in the study and during the study, and any over-the-counter drug, vitamin or herbal preparation for 10 days prior to participation in the study and during the study.

The screening procedure was completed within 21 days prior to the first phase of clinical approval. For each of the three study periods, subjects remained isolated for about 24 hours and were given treatment at least 7 days apart, and subjects received a diet according to a special diet that controls niacin and fat content. The diet composition and start time were the same for each study period.

Study treatment

The study drug was orally administered in a crossover fashion according to a randomized protocol. Although the aspirin (ASA) and placebo administrations were different during each study period, the dosage of the two 1000mg coated, sustained release niacin tablets (also referred to herein as "reconstituted niacin ER tablets" or "rNER") of the present invention was the same. In one phase, subjects received two tablets of 325mg aspirin 30 minutes prior to 2000mg reconstituted niacin ER, taken together with two tablets of placebo ("ASA pretreatment"). In another phase, subjects received two placebo tablets, two tablets taken together with 325mg aspirin ("ASA concomitant"), 30 minutes prior to 2000mg reconstituted niacin ER. In phase three, subjects received a control treatment consisting of two placebo tablets taken together ("R-nicotinic acid ER alone") 30 minutes prior to 2000mg of reconstituted nicotinic acid ER.

Because the assessment of flushing events is subjective, researchers and subjects were blinded by several methods to identify the drug administered. During each dosing period, subjects received the same number of tablets for each dose (see fig. 21). While placebo and aspirin tablets were similar in appearance, they were different; thus, study medication was administered from an opaque dosing cup, and subjects were allowed to drape over their eyes during study medication administration. Control treatment (R-niacin ER alone) was included in this study to assess flushing response in the absence of aspirin. Only the sponsor was studied during the study and the members who formulated the doses at each stage in the clinic were aware of the randomized distribution of treatment. Investigators, site personnel, and study monitors are unaware of treatment allocation schedules, and any site personnel involved in treatment preparation or administration are prohibited from collecting or evaluating flushing events or emergency treatment adverse events.

Each subject received a pretreatment medication and snack prior to administration of reconstituted niacin ER. Subjects took the indicated pre-treatment medication (aspirin or placebo) with a 180mL water intake at about 21:30, followed by a low-fat snack at about 21: 45. All snacks were eaten before subjects received the remaining prescribed treatment with 240mL of water at about 22: 00. Each dosage requires multiple tablets and is taken within a minute, e.g., one tablet taken together or one tablet taken next to another at the same time. If the tablet needs to be swallowed, 120mL of water is additionally provided; chewing or biting agents are prohibited. The mouth of each subject was examined after administration of the study dose to confirm that the full dose was taken.

Evaluation of flushing

A flushing event is determined when the subject reports one or more of the following flushing symptoms: redness, fever, tingling and itching; these symptoms may occur separately or simultaneously. Subjects were assessed rapidly for symptoms of flushing or absence every hour during each study period, up to 8 hours after administration of reconstituted niacin ER. The subject's onset time, cessation time and intensity of each flushing symptom were rapidly recorded in an electronic diary.

Each subject was characterized for sensory symptom intensity rating by sequential and categorical measurements. Subjects marked the intensity of symptoms with a vertical line on an electronic horizontal Visual Analog Scale (VAS), anchored from "none" on the left to "intolerable" on the right, and also characterized the grade of symptoms as mild, moderate or severe. Determining symptoms that are easily tolerated and do not limit activity to be mild; the symptoms that lead to difficulty performing the activity are severe.

Each subject was similarly rated for the first total flushing event, as determined by the first one or more concurrent flushing symptoms that occurred following niacin ER administration. The onset time of the first symptom is also the onset time of the first full flush event; the end of the total event was considered when the last symptom resolved in that event and no additional flushing symptoms occurred over at least 30 minutes.

Statistical analysis

A total of 164 subjects were enrolled scheduled to ensure that at least 144 subjects would complete all three treatments. Subjects with early discontinuation were not replaced.

All comparisons were made with a ═ 0.05, two tailed. The primary endpoint is the number of subjects who experienced at least one flushing event during the study. The incidence of flushing was compared between "ASA pretreatment" and control treatment ("R-niacin ER alone") using McNemar's test. This test requires the subject to respond (in this case, flushing) after both treatments included in the comparison. Comparisons of incidence of flushing were similarly made between "ASA concomitant" and "R-nicotinic acid ER alone" treatments, "ASA pretreatment" and "ASA concomitant" treatments.

The secondary endpoints included the number of flushing events, and the first total flushing event, as well as the intensity, onset time, and duration of each flushing symptom. The number of events was summarized by frequency counting and compared using McNemar's test. VAS intensity evaluations were converted from graphs to data by expressing the subject's vertical marker as a distance (normalized to 100mm) from the left end of the VAS line. The intensity and duration measured by VAS were compared between treatments using the mean paired t test and median Wilcoxon signed rank test, while the intensity measured by class scale was compared using the symmetric Bowker test (generalization of McNemar's test), which also requires that subjects have data for both treatments compared. Comparisons between secondary endpoint treatments were made using the same treatment pairings as the primary endpoint.

Medical Dictionary for Regulatory Activities (MedDRA, version 7.0) was used to encode adverse events (except for tidal Infrared). Adverse events between treatments were not compared.

Results

Mean age 29 years and mean BMI 26.5kg/m²A total of 164 men were enrolled and received at least one dose of study medication. The demographics of the subjects are summarized in table 26. Of the 164 subjects, 148 (90%) received all three treatments and the flushing response could be assessed. Early termination in 16 subjects (10%): 4 subjects (2%) required withdrawal, 4 (2%) were lost in follow-up observations, 1 (1%) had adverse events, 3 (2%) had violations, 3 (2%) drug screens were positive, and 1 (1%) was discarded due to dosing errors.

Table 26: demographics of baseline subjects

BMI-body mass index

Flushing with hot flashes

In 148 subjects receiving all three treatments, the incidence of flushing after "R-nicotinic acid ER alone" (77%) was significantly higher than the incidence of flushing after "concomitant ASA" (61%, p <0.001) or "ASA pretreatment" (53%, p < 0.001; Table 27).

Table 27: effect of Aspirin on incidence of flushing

^*p<0.001 comparison with R-nicotinic acid ER alone

p ═ 0.090 compared to the accompanying ASA

Aspirin-containing treatments were not significantly different in incidence of flushing from other treatments. As shown in figure 21, the incidence of each symptom (redness, fever, tingling, and itching) was reduced by 30% -50% in the first all flushing events after "ASA pretreatment" compared to "R-nicotinic acid ER alone". After "ASA pretreatment", the number of subjects reporting all four symptoms was the least, the most after "R-nicotinic acid ER alone". The symptoms were not compared between treatments. The number of flushing events followed the same trend as the incidence of flushing, with the highest number reported after "R-niacin ER alone" and the lowest number reported after "ASA pretreatment" (data not shown).

In subjects with flushing following "ASA pretreatment" and "R-niacin ER alone" treatment (table 28 below), "ASA pretreatment" significantly reduced the intensity of the first all flushing events as measured by either categorical evaluation or VAS (individual P < 0.001).

TABLE 28 Effect of Aspirin pretreatment on first Total flushing events

^*Percent difference compared to niacin ER alone.

McNemar's test from incidence and intensity (categorical), intensity (VAS) and duration; from paired t-test or Wilcoxon signed rank test (mean or median data, respectively).

The nominator (Denominator) is the number of flushing subjects after both treatments.

Combine moderate and severe classifications to allow a2 x 2 comparison. No subject reported a severe event after treatment with ASA pretreatment; one subject reported severe events following R-nicotinic acid ER treatment alone.

For both treatments, most flushing events were rated mild, with only one case (after "R-niacin alone ER") being severe. 36% more subjects were rated as mild events after "ASA pretreatment" compared to "R-nicotinic acid ER alone"; accordingly, the number of subjects with moderate or severe flushing was determined to be 62% less. VAS grading after "ASA pretreatment" was more than 30% lower than after "R-nicotinic acid ER alone". For the duration of the first all flushing events, the mean and median values are inconsistent, suggesting a non-normal distribution. "ASA pretreatment" had a median duration 43% less than "R-nicotinic acid ER alone" (p ═ 0.008). The intensity of redness, fever and tingling for each symptom was significantly reduced after "ASA pretreatment" (p.ltoreq.0.025, data not shown); there was no significant difference in the duration of any symptoms between treatments.

In subjects with flushing following "concomitant ASA" and "R-niacin ER alone" treatment (table 29 below), there was a significant difference in categorical data for the intensity of the first all flushing events, although there was no VAS data (p ═ 0.028).

Table 29: effect of Simultaneous Aspirin on first Total flushing event

^*Percent difference compared to niacin ER alone.

McNemar's test from incidence and intensity (categorical), intensity (VAS) and duration; from paired t-test or Wilcoxon signed rank test (mean or median data, respectively).

The nominations are the number of flushing subjects after both treatments.

Combine moderate and severe classifications to allow a2 x 2 comparison. No subject reported a severe event after treatment with ASA pretreatment; one subject reported severe events following R-nicotinic acid ER treatment alone.

Here, the number of subjects with mild flushing events after "concomitant ASA" treatment was 22% higher than after "R-niacin ER alone", while moderate or severe events were 38% less. The difference in duration of the first total flushing event was not significant. For each symptom, the intensity of redness and fever was significantly reduced after "concomitant ASA" treatment (p ≦ 0.024, data not shown); there was no significant difference in the duration of any symptoms.

In subjects with flushing following both "ASA pretreatment" and "concomitant ASA" treatments (see table 30 below), there was no significant difference in the intensity of the first total flushing event, as measured by classification, but a 20% reduction in the VAS score of "ASA pretreatment" was statistically significant.

Table 30: effect of Aspirin (before or with reconstituted Niacin ER) on first Total flushing events

^*Percent difference relative to the accompanying ASA.

McNemar's test from incidence and intensity (categorical), intensity (VAS) and duration; from paired t-test or Wilcoxon notationRank test (mean or median data, respectively).

The nominations are the number of flushing subjects after both treatments.

Severe event reporting without these treatments.

There was no significant difference in the duration of the first total flushing event between these treatments. There were no significant differences in the intensity or duration of each symptom between the two treatments.

The above results show that: administration of 650mg (2 x 325mg tablets) of aspirin 30 minutes prior to the extended release tablet of the present invention significantly reduced the incidence, intensity and duration of flushing reported by the subjects compared to the tablets of the present invention alone. Simultaneous administration of 650mg aspirin and the tablet of the present invention reduced the incidence, intensity and duration of flushing to a lesser extent.

The incidence and intensity of flushing caused by examples 3 and 8 are collectively summarized and illustrated in figures 22 and 23. These figures show that: although there was a small reduction in the incidence of flushing, the tablets were compared with the original 1000mg tabletsIn contrast, the sustained release pharmaceutical composition of the present invention reduced the flush intensity and duration (-40%) -see example 3. Example 8 shows that: aspirin taken 30 minutes prior to or with the sustained release pharmaceutical composition of the present invention may reduce the incidence of flushing and further provide a reduction in flushing intensity and duration. In example 3, using a single dose of 2000mg of the original 1000mg tablet (two-tablet dose), flushing (incidence) is reported in almost all patients (98%). In example 8, using a single dose of 2000mg of the sustained release tablet of the present invention (two tablet dose) plus aspirin, only 50-60% of patients experienced flushing. In previous studies, the median VAS intensity was 54mm with the original 1000mg tablet. In the present study, the sustained-release tablet of the present invention was usedThe median intensity of aspirin added was only 19-23mm, and most (about 80% or more) reported that flushing was "mild".

While the invention has been described above in connection with specific embodiments thereof, it is evident that many alternatives, 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. All patent applications, patents, and other publications cited herein are incorporated by reference in their entirety.

Claims (77)

1. A 1000mg niacin pharmaceutical composition comprising:

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

(b) from about 14% to about 18% w/w hydroxypropyl methylcellulose having a methoxyl degree of substitution of from about 1.39 to about 1.41 and a hydroxypropoxyl molar substitution of from about 0.20 to about 0.22;

(c) from about 2.5% to about 3.0% w/w polyvinylpyrrolidone, and

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

2. A pharmaceutical composition comprising:

(a) from about 70% to about 92% w/w niacin;

(b) about 7% to about 25% w/w of a delayed release agent;

(c) from about 0.1% to about 4.3% w/w binder, and

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

wherein the NIASPAN is administered in a dose equivalent to the administrationThe composition results in reduced flushing compared to tablets following administration to a patient.

3. The pharmaceutical composition of claim 2, which is a 1000mg extended release niacin tablet.

4. The pharmaceutical composition of claim 3, which is effective to reduce blood lipids without causing treatment limitations (i) hepatotoxicity and (ii) elevated uric acid levels or glucose levels, or both, which would require discontinuation of such treatment after administration to the patient when the composition is ingested by the patient 1 time/day.

5. The pharmaceutical composition of claim 4, wherein the patient is administered at night or 1 time/day in the evening.

6. The pharmaceutical composition of claim 2, wherein the release retarding agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose), Methylcellulose (MC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP) and xanthan gum and mixtures thereof.

7. The pharmaceutical composition of claim 6, wherein the delayed release agent is hydroxypropyl methylcellulose.

8. The pharmaceutical composition of claim 7 wherein the hydroxypropyl methylcellulose has a methoxy degree of substitution of about 1.2 to about 2.0 and a hydroxypropoxy molar substitution of about 0.1 to about 0.3.

9. The pharmaceutical composition of claim 8 wherein the hydroxypropyl methylcellulose has a methoxy degree of substitution of about 1.4 to about 1.9 and a hydroxypropoxy molar substitution of about 0.19 to about 0.24.

10. The pharmaceutical composition of claim 8 wherein the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.4 and a hydroxypropoxyl molar substitution of about 0.21.

11. The pharmaceutical composition of claim 8 wherein the hydroxypropyl methylcellulose has a viscosity of about 11,000 to about 22,000 mPas.

12. The pharmaceutical composition of claim 11 wherein the hydroxypropyl methylcellulose has a viscosity of about 13,000 to about 18,000 mPas.

13. The pharmaceutical composition of claim 2, further comprising a coating.

14. The pharmaceutical composition of claim 13, wherein the coating is a colored coating having a weight gain of about 1.5% to about 8.0%.

15. The pharmaceutical composition of claim 14, wherein the coating is a colored coating applied to the tablet to provide about a 1.75% to about a 5.0% weight gain.

16. The pharmaceutical composition of claim 7, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethacrylates and waxes or mixtures thereof.

17. The pharmaceutical composition of claim 16, wherein the binder is polyvinylpyrrolidone.

18. The pharmaceutical composition of claim 7 wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oils and mixtures thereof.

19. The pharmaceutical composition of claim 18, wherein the lubricant is stearic acid.

20. The pharmaceutical composition of claim 2, comprising:

(a) from about 76% to about 88% w/w niacin;

(b) from about 11.0% to about 20.0% w/w of a delayed release agent;

(c) from about 0.2% to about 3.25% w/w binder, and

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

21. The pharmaceutical composition of claim 20, comprising:

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

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

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

(d) about 0.85% to about 1.05% w/w of a lubricant.

22. The pharmaceutical composition of claim 21 comprising from about 0.95% to about 1.05% w/w of the lubricant.

23. A method of reducing flushing associated with niacin therapy, comprising administering 1 time per day a pharmaceutical dosage form comprising:

(a) from about 70% to about 92% w/w niacin;

(b) about 7% to about 25% w/w of a delayed release agent;

(c) from about 0.1% to about 4.3% w/w binder, and

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

24. The method of claim 23, wherein the 1 time/day dosage form comprises 2 1000mg tablets.

25. The method of claim 23, wherein the tablet is a 1000mg tablet, the 1000mg tablet comprising:

(a) from about 76% to about 88% w/w niacin;

(b) from about 11.0% to about 20.0% w/w of a delayed release agent;

(c) from about 0.2% to about 3.25% w/w binder, and

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

26. The method of claim 25, wherein the 1000mg tablet comprises:

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

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

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

(d) about 0.85% to about 1.05% w/w of a lubricant.

27. The method of claim 26, wherein the 1000mg tablet comprises about 0.95% to about 1.05% w/w lubricant.

28. The method of claim 23, wherein the delayed release agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose), Methylcellulose (MC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), co-polymerization of methacrylate and trimethylammonioethyl methacrylateArticle (EUDRAGIT RS)、EUDRAGIT RL) And xanthan gum and mixtures thereof.

29. The method of claim 28, wherein the delayed release agent is hydroxypropyl methylcellulose and the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.2 to about 2.0 and a hydroxypropoxyl molar substitution of about 0.1 to about 0.3.

30. The method of claim 29 wherein the hydroxypropyl methylcellulose has a methoxy degree of substitution of about 1.4 to about 1.9 and a hydroxypropoxy molar substitution of about 0.19 to about 0.24.

31. The method of claim 30 wherein the hydroxypropyl methylcellulose has a methoxyl degree of substitution of about 1.4 and a hydroxypropoxyl molar substitution of about 0.21.

32. The method of claim 29 wherein the hydroxypropyl methylcellulose has a viscosity of from about 11,000 to about 22,000 mPas.

33. The method of claim 32 wherein the hydroxypropyl methylcellulose has a viscosity of about 13,000 to about 18,000 mPas.

34. The method of claim 23, wherein the pharmaceutical dosage form further comprises a coating.

35. The method of claim 34, wherein the coating is a colored coating applied to the pharmaceutical dosage form to provide a weight gain of about 1.5% to about 8.0%.

36. The method of claim 35, wherein the coating is a colored coating applied to the pharmaceutical dosage form to provide a weight gain of about 1.75% to about 5.0%.

37. A method of making a direct compressed niacin tablet comprising the steps of:

(a) blending a mixture of: from about 70% to about 92% w/w niacin, from about 7% to about 25% w/w delayed release agent, from about 0.1% to about 4.3% w/w binder, and from about 0.5% to about 1.5% w/w lubricant;

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

38. The method of claim 37, wherein said niacin tablet is a 1000mg niacin dosage formulation.

39. The method of claim 37, further comprising coating the tablet.

40. The method of claim 37, further comprising coating said tablet with a colored coating agent to provide said tablet with a weight gain of about 1.5-8.0%.

41. The method of claim 40, wherein said colored coating has a weight gain of about 1.75-5.0%.

42. The method of claim 40, wherein the delayed release agent is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose), Methylcellulose (MC), hydroxyethyl cellulose (HEC), polyvinylpyrrolidone (PVP), copolymers of methacrylate and trimethylammonioethyl methacrylate (EUDRAGIT RS)、EUDRAGIT RL) And xanthan gum or mixtures thereof.

43. The method of claim 40, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polymethacrylates, and waxes, or mixtures thereof.

44. The method of claim 40, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid and hydrogenated vegetable oils or mixtures thereof.

45. The method of claim 40, wherein said tablet comprises from about 76% to about 88% w/w niacin, from about 11.0% to about 20% w/w delayed-release agent, from about 0.2% to about 3.25% w/w binder, and from about 0.75% to about 1.25% w/w lubricant.

46. The method of claim 45, wherein said tablet comprises from about 78% to about 82% w/w niacin, from about 14% to about 18% w/w delayed-release agent, from about 2.5% to about 3.0% w/w binder, and from about 0.95% to about 1.05% w/w lubricant.

47. The method of claim 37, wherein the delayed release agent is hydroxypropyl methylcellulose, the binder is polyvinylpyrrolidone, the lubricant is stearic acid, and wherein the hydroxypropyl methylcellulose has a methoxy degree of substitution of about 1.2 to about 2.0 and a hydroxypropoxy molar substitution of about 0.1 to about 0.3.

48. A direct compressed 500mg niacin sustained release tablet comprising:

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

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

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

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

49. The direct compressed 500mg niacin sustained release tablet of claim 48, comprising:

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

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

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

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

50. The direct compressed 500mg niacin sustained release tablet of claim 48, further comprising a coating, wherein the coating has a weight gain of about 1.5% to about 8.0%.

51. A direct compressed 750mg niacin sustained release tablet comprising:

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

(b) about 16% to about 22% w/w of a delayed release agent;

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

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

52. The direct compressed 750mg niacin sustained release tablet of claim 51, comprising:

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

(b) about 18% to about 21% w/w of a delayed release agent;

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

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

53. The direct compressed 750mg niacin sustained release tablet of claim 52, further comprising a coating, wherein the coating has a weight gain of about 1.5% to about 8.0%.

54. The pharmaceutical composition of claim 2, further comprising an antilipidemic agent.

55. The pharmaceutical composition of claim 54, wherein the antilipidemic drug is an HMG-CoA reductase inhibitor.

56. The pharmaceutical composition of claim 55, further comprising a flushing inhibitor.

57. The pharmaceutical composition of claim 2, further comprising a flushing inhibitor.

58. The pharmaceutical composition of claim 57, wherein the flushing inhibitor is a non-steroidal anti-inflammatory drug (NSAID).

59. The pharmaceutical composition of claim 58, wherein the flushing inhibitor is aspirin (ASA).

60. The pharmaceutical composition of claim 57, wherein the flushing inhibitor is prostaglandin D₂A receptor antagonist.

61. The pharmaceutical composition of claim 60, wherein the prostaglandin D is₂The receptor antagonist is MK-0524.

62. The method of any one of claims 23, 37, 48 or 51 wherein said niacin is particulate niacin.

63. The method of claim 62 wherein the particle size of said particulate niacin is sieve size grade 100-.

64. A 1000mg extended release niacin pharmaceutical composition that, when administered to a patient in need thereof as a single 2-tablet 1000mg tablet, provides an in vivo plasma profile within 80% -125% of the 90% CI of the natural log-conversion rate of at least 1 of the following bioavailability parameters:

(a)2601.8ng/mL NUA C_max；

(b) Total recovery of urinary niacin of 60.5%;

(c)4958.9ng/mL niacin C_max(ii) a And

(d) niacin AUC of 12414.5 ng/mL.

65. The 1000mg extended release niacin pharmaceutical composition of claim 64, wherein said natural log conversion rate is within the range of 90% to 115%.

66. The 1000mg extended release niacin pharmaceutical composition of claim 64, wherein said natural log conversion rate is within the range of 95% -110%.

67. The 1000mg extended release niacin pharmaceutical composition of claim 64, further comprising at least one additional therapeutic agent selected from the group consisting of a flushing inhibitor and an antilipidemic drug.

68. The 1000mg extended release niacin pharmaceutical composition of claim 77, wherein said composition is effective for reducing blood lipids without causing a treatment limitation (i) hepatotoxicity and (ii) elevated uric acid levels or glucose levels, or both, which would require discontinuation of such treatment when said composition is ingested by said patient 1 time/day.

69. A1000 mg extended release niacin pharmaceutical composition, when administered to a subject in a bioequivalence study, as a single dose of 4 tablets of 500mg NiASPANThe nature of the tablet provides appropriate bioavailability parameters compared to a single dose of the 1000mg extended release niacin compositionLog conversion rate 90% CI in the interval 80% -125%.

70. The 1000mg extended release niacin pharmaceutical composition of claim 69, wherein said bioavailability parameter is NUA C_max(ng/ml) and total recovery, or niacin C_max(ng/ml) and niacin AUC.

71. A 1000mg extended release niacin pharmaceutical composition that, when administered to a patient in need thereof as a single 2-tablet 1000mg tablet, provides an in vivo plasma profile with 90% CI over an interval of 80% -125% of the natural log-conversion rate of at least 1 of the following bioavailability parameters:

(a) NUA C of about 2111.0ng/mL to about 3253ng/mL_max；

(b) A total recovery of urinary niacin of about 49.24% to about 70.23%;

(c) nicotinic acid C from about 3096ng/mL to about 6750ng/mL_max(ii) a And

(d) niacin AUC of about 6723ng/mL to about 18643 ng/mL.

72. The 1000mg extended release niacin pharmaceutical composition of claim 71, wherein said composition is effective for reducing blood lipids without causing a treatment limitation of (i) hepatotoxicity and (ii) elevated uric acid levels or glucose levels, or both, which would require discontinuation of such treatment when said composition is ingested by said patient 1 time/day.

73. The pharmaceutical composition of claim 3 wherein the release of niacin is delayed.

74. The pharmaceutical composition of claim 73, further comprising an immediate-release flushing inhibitor.

75. The pharmaceutical composition of claim 74, wherein the flushing inhibitor is prostaglandin D₂A receptor.

76. The pharmaceutical composition of claim 75, wherein the prostaglandin D is₂The receptor is MK-0524.

77. The pharmaceutical composition of claim 74, wherein the flushing inhibitor is a non-steroidal anti-inflammatory drug (NSAID).