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WO2008100249A1 - Formulation de niacine à faible bouffée vasomotrice - Google Patents

Formulation de niacine à faible bouffée vasomotrice Download PDF

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Publication number
WO2008100249A1
WO2008100249A1 PCT/US2007/003659 US2007003659W WO2008100249A1 WO 2008100249 A1 WO2008100249 A1 WO 2008100249A1 US 2007003659 W US2007003659 W US 2007003659W WO 2008100249 A1 WO2008100249 A1 WO 2008100249A1
Authority
WO
WIPO (PCT)
Prior art keywords
niacin
tablet
lubricant
dosage form
retarding agent
Prior art date
Application number
PCT/US2007/003659
Other languages
English (en)
Inventor
Jose G. Rocca
Yucun Zhu
Eugenio A. Cefali
Original Assignee
Kos Life Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kos Life Sciences, Inc. filed Critical Kos Life Sciences, Inc.
Priority to PCT/US2007/003659 priority Critical patent/WO2008100249A1/fr
Publication of WO2008100249A1 publication Critical patent/WO2008100249A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to an extended release matrix formulation capable of being directly compressed into tablets comprising niacin, a release retarding agent, and other excipients.
  • the resulting tablets of the invention demonstrate favorable release characteristics and a reduction in the incidences of cutaneous flushing commonly associated with niacin treatment.
  • Niacin (nicotinic acid, also known as 3-pyridinecarboxylic acid, chemical formula QH5NO 2 ) is known to have benefits associated with the treatment of hypercholesterolemia because it increases levels of high density lipoproteins (HDL) and lowers levels of total serum cholesterol low density lipoproteins (LDL) and triglycerides.
  • HDL high density lipoproteins
  • LDL total serum cholesterol low density lipoproteins
  • niacin is known to provide a very beneficial effect on blood lipids, with the exception of Niaspan®, widespread use of niacin is limited due to the high incidence of "flush” that often occurs with higher doses of niacin needed for effective lipid treatment. Flushing is a term generally used to describe prostaglandin-mediated vasodilatation. As a result, an individual experience flushing may develop a visible, uncomfortable hot or flushed feeling upon administration of niacin. While certain materials and/or formulations have been suggested for avoiding or reducing cutaneous flushing (see US Pat.
  • the present invention provides for an direct compression, extended release (ER) matrix tablet formulation comprising niacin and a release retarding agent.
  • ER extended release
  • the present invention provides a pharmaceutical tablet comprising:
  • the present invention provides for method of preparing the extended release niacin tablets which comprises the steps of
  • step (b) compressing the mixture of step (a) into a tablet.
  • the present invention further provides a once daily niacin pharmaceutical dosage form, said dosage form providing, when administered as a single dose of two 1000 mg tablets to a subject, in vivo NUA plasma profile characterized by at least one of the following
  • Figure 1 is illustrates a flow-diagram of a direct compression manufacturing process for preparing the tablet formulations in accordance with, an embodiment of the invention.
  • Figure 2 is a chart illustrating a reduction in the overall intensity of flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®)
  • Figure 3 is a chart illustrating a reduction in the overall duration of flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • Figure 4 is a chart illustrating a reduction in subjects experiencing flush using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • Figure 5 is a chart illustrating a reduction in the incidence of multiple flushing symptoms for subjects using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • Figure 6 is a chart illustrating the mean plasma concentrations of niacin using the extended-release niacin tablets of the present invention.
  • Figure 7 is a chart illustrating the mean plasma concentrations of nicotinuric acid (NUA) using the extended-release niacin tablets of the present invention.
  • the extended release matrix tablet formulations of the present invention include niacin as an active ingredient and a hydrophilic polymer matrix for achieving controlled, extended release of the active ingredient, i.e., a release retarding agent
  • a hydrophilic matrix, controlled-release system involves polymer wetting, polymer hydration, gel formation, swelling and polymer dissolution. Soluble drugs in the matrix also wet, dissolve and diffuse out of the matrix. Although the mechanism by which soluble drugs are released in matrix tablets are dependent on many variables, the main principle is that the water-soluble polymer, present throughout the tablet, hydrates on the outer tablet surface to form a gel layer. As water permeates into the tablet, the gel layer increases in thickness and the soluble drug diffuses through the gel layer. During the life of the ingested tablet, the rate of drug release is determined by diffusion of the soluble drug through the gel and by the rate of tablet erosion.
  • the hydrophilic component of the present invention may be any hydrophilic release retarding agent that demonstrates favorable swelling and gelling properties, such as those known to those skilled in the art.
  • the release retarding agent will typically be present in the tablets of the present invention at a concentration of about 10% to about 25% w/w (percent weight relative to total weight of the formulation), preferably about 12.5% to about 20% w/w, more preferably about 14% to about 18% w/w.
  • suitable release retarding agents include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyhnethyl cellulose (HPMC or hypromellose), methylceUulose (MC), hydroxyethyf cellulose (HEC) and polyvinyl pyrrolidone (PVP) 3 xanthan gum, as well as mixtures of these release retarding agents.
  • HPC hydroxypropyl cellulose
  • HPMC or hypromellose HPMC or hypromellose
  • MC methylceUulose
  • HEC hydroxyethyf cellulose
  • PVP polyvinyl pyrrolidone
  • the release retarding agent is hydroxypropylmethyi cellulose.
  • HPMC has a polymeric backbone of cellulose, a natural carbohydrate that contains a basic repeating structure of anhydrogiucose units.
  • the hydration rate (i.e., the drug release rate) of HPMC will differ as a result of varying proportion of the two chemical substituents, hydroxypropyl and methyl substitution, attached to the cellulose backbone of HPMC
  • the hydroxypropyl substitution is relatively hydrophilic in nature and greatly contributes to the rate of hydration, while the methoxyl substitution is relatively hydrophobic in nature.
  • the amount of substituent groups on the anhydrogiucose units of cellulose can be designated by the average number of substituents groups attached to a single anhydrogiucose ring, a concept commonly known to those skilled in the art as 'degree of substitution". See "Methocel® Cellulose Ethers Technical Handbook, Dow Chemical Company.
  • the HPMC release retarding agent has a methoxyl degree of substitution of about 1.2 to about 2.0 and a hydroxypropyl molar substitution of about 0.1 to about 0.3, preferably a methoxyl degree of substitution of about 1.4 to about 1.9% and a hydroxypropyl molar substitution of about 0.21 to about 0.23, more preferably a methoxyl degree of substitution of about 1.4 to about 1.45 and a hydroxypropyl molar substitution of about 0.21 to about 0.215.
  • HPMC viscosity (determined in water at 20° C, with a concentration of 2%, e.g., ASTM D2363) is about 11,000 to about 22,000 Millipascal (mPas), preferably about 13,000 to about 18,000 MiUipascal (mPas).
  • Niacin a water soluble medicament
  • Niacin is commercially available as fine white crystals, granular or white crystalline powder.
  • Niacin will typically be present in the tablets of the present invention at a concentration of 70% to 95% w/w, preferably 70% to 90% w/w, more preferably 78% to 82% w/w.
  • the tablets of the present invention further comprise a binder.
  • the binder may be any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone (also known as PVP, povidone, polyvidone), hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used.
  • the binder comprises about 1.3% to 4.3% w/w of the total weight of the tablet, preferably about 2.0% to 3.25% w/w, more preferably about 2.5% to 3.0% w/w.
  • the tablets of the present invention comprise a lubricant.
  • the lubricant may be hydrophobic or hydrophilic and include lubricants commonly known to those in the art, such as, but not limited to talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and the like.
  • the lubricant is stearic acid.
  • Lubricant addition helps to reduce the friction between the die wall and tablet formulation during compression and aids in the flow of powder (i.e., the flow of mixed formulation into the hopper and die) and helps to prevent adhesion of tablet material to processing equipment.
  • the tablet formulations of the invention comprise about 0.5% to 1.5% w/w of a lubricant, preferably about 0.75% to 1.25% w/w, more preferably, about 0.85% to 1.15% w/w, more preferably, about 0.95% to 1.05% w/w.
  • the extended release tablet formulations of the invention may further include a coating, such as an Opadry® type coating, as are known to those skilled in the art, and may be applied from solution (e.g., aqueous) or suspension using any known means, such as a fluidized bed coater (e.g., Wurster coating) or pan coating system.
  • coating is a color coating having from about 1.5 to about 8.0% weight gain, preferably from about 1.75 to about 5.0% weight gain.
  • Figure 1 illustrates a flow-diagram of a direct compression manufacturing process for preparing the tablet formulations in accordance with an embodiment of the invention.
  • niacin granular and the excipients were weighed according to the above formula and then added into an 8 quart blender and blended for 10 minutes.
  • the resultant granular composition was directly compressed into tablets using a BWI Manesty Beta Press with a 19 mm length oval tooling at 30 kN.
  • the stearic acid or povidone may be screened through a mesh screen, such as a 40 mesh screen, and mixing steps (one or two) and mixing time (10, 15 or 20) can be varied in alternate embodiments.
  • the resulting compressed tablets were coated with a 2% weight gain color coat of Opadry® Orange 03B93199.
  • the coating conditions were as follows:
  • the coated niacin 1000 mg direct compression tablets were found to be stable for three months at 40°C/75% relative humidity (RH) and 25°C/60% RH by comparing the niacin assay, niacin dissolution, moisture of the tablets and the physical appearance of the coated tablets prior to and following the stability study.
  • RH relative humidity
  • 500 mg and 750 mg extended-release direct compression tablets may be prepared having content concentrations illustrated in Tables 3 and 4 below.
  • delumped niacin granular and the excipients would be weighed according to the component concentrations illustrated in Tables 2 and 3 and then blended in a suitable blender or mixer for an appropriate time to adequately mix the components.
  • the resultant granular compositions could then be directly compressed into tablets using a suitable press, such as the BWT Martesty Beta Press described above, to form a 500 mg or 750 mg tablet as desired.
  • the 500 mg and 750 mg tablets may be coated, such as with a color coat, as is known in the art.
  • the present study was conducted to compare the incidence of flush associated with the administration of 1000 mg coated, extended-release niacin tablets of the present invention versus commercially available 1000 mg Niaspan® tablets (uncoated).
  • the study measured the incidence of flushing associated with the administration of niacin as a single, 2000 mg dose of a) two 1000 mg coated, extended-release niacin tablets of the present invention plus two uncoated placebo tablets (Test), b) two commercially available 1000 mg Niaspan® tablets plus two coated placebo (Reference), c) two coated placebo tablets plus 2 uncoated placebo tablets (Control).
  • Intensity and duration of symptoms associated with the first flushing event or episode, intensity and duration of the first flushing episode overall, and of subsequent flushing symptoms was also assessed.
  • a flushing event or episode was described as one or more of the following concurrent flushing symptoms: redness, warmth, tingling, and itching.
  • the study was a randomized, single-center, double-blind, double-dummy, randomized, placebo-controlled, single-dose, three-way crossover study in 156 healthy, non-smoking men, 30 to 70 years (yrs)-of-age, inclusive. Dropouts were not replaced. Study medication was administered orally with a minimum washout period of 7 days between each treatment administration: 2000 mg niacin on two separate occasions and placebo control once (uncoated and coated).
  • Each dose was administered with 240 milliliters (mL) of water after a low-fat snack at approximately 22:00 in the evening.
  • Each, subject also rated intensity overall of the first flushing event or episode, defined as beginning at the start time of the first of one or more concurrent flushing symptoms to occur in a treatment period.
  • the end time of that flushing episode was defined as the last stop time of one or more concurrent flushing symptoms occurring in that episode that was also followed by a symptom-free period lasting a minimum of 30 min.
  • the subject After rating intensity overall of the first flushing episode, the subject characterized each recurrence of a flushing symptom in the same study period by entering the start/stop times and marking a vertical line on a visual analog scale for symptom intensity. No additional assessments of intensity were made.
  • the flushing analysis population is defined as subjects who received at least one dose of study medication, and experienced at least one flushing event, or who were evaluated without a flushing event for 8 hours and participated in at least two study periods.
  • TEST 2 X lOOOmg coated, reformulated niacin extended-release tablets plus 2X uncoated placebo tablets (Treatment A).
  • REF 2 X 1000 mg Niaspan ⁇ tablets plus 2X coated placebo tablets (Treatment B)
  • TEST vs. REF Matched paired T-Test (O.0001).
  • Figure 3 illustrates a 43% reduction in the overall duration of flush (p ⁇ 0.0001) using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • TEST 2 X 1 OOOmg coated, reformulated niacin extended-release tablets plus 2 X uncoated placebo tablets; REF: 2 X lOOOmg Niaspan® tablets plus 2 X coated placebo tablets.
  • Mcnemar's Test (0.0027) comparing the number of subjects who flushed on one treatment but not the other, for both treatments.
  • Figure 4 illustrates a 9% reduction in subjects experiencing flush (p ⁇ 0.0027) using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • the flushing analysis population is defined as subjects who received at least one dose of study meciation, and experienced at least one flushing event, or who were evaluated without a flushing event for 8 hours and participated in at least two studies.
  • b- TEST 2 X lOOOmg coated, reformulated niacin extended-release tablets plus 2 X uncoated placebo tablets (Treatment A); REF 2 X 1000 mg Niaspan® tablets plus 2 X coated placebo tablets (Treatment B).
  • c- McNemar's Test 2 X lOOOmg coated, reformulated niacin extended-release tablets plus 2 X uncoated placebo tablets (Treatment A); REF 2 X 1000 mg Niaspan® tablets plus 2 X coated placebo tablets (Treatment B).
  • Figure 5 illustrates a reduction in the incidence of multiple flushing symptoms for subjects using the extended-release niacin tablets of the present invention as compared to existing therapy (Niaspan®).
  • the extended-release niacin tablets of the present invention provides an 17.4% reduction in redness (p ⁇ 0.0016), a 14.2% reduction in incidences of warmth (p ⁇ 0.0163), a 24.1 % reduction in incidences of tingling (p ⁇ 0.0039) and a 25.6% reduction in incidences of itching (p ⁇ 0.0015).
  • the 1000 rag coated, extended-release niacin tablets of the present invention were administered to individuals/study groups in order to evaluate the bioavailability of the niacin tablets.
  • This bioavailability study was a randomized, single-center, open-label, single-dose, two- way crossover in 44 healthy, non-smoking male and female volunteer subjects, 40 to 70 years- of-age, inclusive. Drop-outs were not replaced.
  • Each eligible subject received two treatments (Treatment A or Test, and Treatment B or Reference), which were separated by a minimum 10-day washout, in two periods.
  • Treatment A subjects received two 1000 mg coated reformulated extended-release, niacin tablets (made in accordance with the present invention- Test) and in Treatment B subjects received two of the 1000 mg uncoated reformulated, extended-release niacin tablets (made in accordance with the present invention-Reference).
  • Serial blood samples were collected within 30 min prior to dosing and through 24 hrs after dosing in each period (15 samples/treatment). Each blood sample was collected into one 17-mL vacutainer containing sodium heparin and was allowed to cool in an ice-chip and water bath for a minimum of 5 min after collection. Samples were centrifuged at 4° C at approximately 3000 rpm for 15 min to separate the plasma. Samples were then stored frozen at approximately -20° C until shipped on dry ice to an independent contractor for niacin and NUA analysis.
  • Niacin and nicotinuric acid (NUA) concentrations was analyzed by validated liquid chromatography tandem mass spectroscopy (LC/MS/MS). Both niacin and NUA concentrations were obtained from the same injection. The lower limit of quantitation (LLQ) for both niacin and NUA was 2 ng/mL in plasma. Quality control samples were evaluated with each analytical run.
  • LC/MS/MS liquid chromatography tandem mass spectroscopy
  • Urine was collected for the following intervals: -24 to -18, -18 to -12, -12 to -6, -6 to 0 hrs ⁇ prior to dosing), and 0 to 6, 6 to 12, 12 to 18, 18 to 24, 24 to 48, 48 to 72, 72 to 96 hrs after dosing (for a total of 11 collections).
  • Urine was collected and transferred into plastic containers equipped with tightly fitting lids. Collected urine was kept refrigerated or in an ice-water bath during the collection interval.
  • the collection containers were labeled to identify the subject number and initials, collection interval, and protocol number.
  • the empty containers were weighed to the nearest tenth of a gram (e.g., 100.1 g) and this was written on the container and documented on the lab's source document worksheets. At the end of each interval, the total weight of the container and the collected urine was measured to the nearest tenth of a gram and recorded. The weight of the urine was derived by subtracting the weight of the empty container from the total weight of the container plus the urine.
  • the volume of urine during a given collection interval exceeded the capacity of a single container; therefore a second container was required to obtain a complete urine collection.
  • the start and stop date(s) and times of each urine collection interval were also recorded. Samples were stored frozen at approximately -20 ° C until shipped on dry ice an independent contractor for analysis.
  • Urine samples were analyzed for concentrations of niacin, NUA, N-methylnicotinamide (MNA) and N-methyl-2-pyridone-5-carboxamide (2PY) by validated LC/MS/MS; Urine niacin and NUA concentrations were obtained from the same injection while MNA and 2-PY concentrations were obtained from the same injection.
  • the LLQ values were 20 ng/mL for niacin and 200 ng/mL for MJA.
  • MNA and 2PY had LLQ values of 500 ng/mL and 2500 ng/mL, respectively. Quality control samples were evaluated with each analytical run.
  • a specific gravity of 1 g/mL was used to convert urine weights to volumes. This was based on a previous study with Niaspan® where the mean specific gravity measured in 962 samples was 1.009 g/mL and the maximum specific gravity measured in 962 samples was 1.025 g/mL.
  • PK parameters were calculated for each subject following administration of each treatment:
  • ast the area under the concentration-time profile from time 0 to the last measurable (non-zero) concentration by the linear trapezoidal rule
  • bioavailability data for the Test and Reference included the construction of 90% confidence intervals for Test/Reference (Treatment A/Treatment B) treatment ratios of natural log-transformed C m a X for NUA and total urine recovery data to determine bioequivalence (BE) between Test and Reference.
  • the ratio and confidence intervals were obtained from the ANOVA model with treatment, period, and treatment sequence as fixed effects, and subject within sequence as a random effect. Confidence intervals within the conventional 80 to 125% limits for NUA C ni ax and total amount of niacin and metabolites excreted in urine were required to conclude BE.
  • Table 5 illustrates mean PK parameters for plasma niacin.
  • test formulation coated reformulated 1000 mg extended release niacin tablet
  • reference formulation coated reformulated 1000 mg extended-release niacin tablet
  • Formulations within the scope of the invention are those that are deemed bioequivalent to the formulations of the invention based on ratios of natural log-transformed Cma x for NUA and total urine recovery data within standard 80% to 125% intervals (See for example, Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations, U.S. Department of Health & Human Sercices, Food and Drug Administration, CDER 5 March 2003) " .
  • such formulations are compared to reference formulations (such as those described herein or the embodiments of the invention described herein) under the same analytical conditions (e.g., analytical and technical conditions for urinary analysis) wherein the reference formula is used as a control.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation à matrice à libération prolongée capable d'être directement comprimée en comprimés comprenant de la niacine, un agent retardant la libération et d'autres excipients. Les comprimés résultants de l'invention démontrent des caractéristiques de libération favorables et une réduction des incidences de bouffée vasomotrice couramment associée au traitement avec de la niacine.
PCT/US2007/003659 2007-02-13 2007-02-13 Formulation de niacine à faible bouffée vasomotrice WO2008100249A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2007/003659 WO2008100249A1 (fr) 2007-02-13 2007-02-13 Formulation de niacine à faible bouffée vasomotrice

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2007/003659 WO2008100249A1 (fr) 2007-02-13 2007-02-13 Formulation de niacine à faible bouffée vasomotrice

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WO2008100249A1 true WO2008100249A1 (fr) 2008-08-21

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126145A (en) * 1989-04-13 1992-06-30 Upsher Smith Laboratories Inc Controlled release tablet containing water soluble medicament
EP0577504A1 (fr) * 1992-06-29 1994-01-05 Upsher-Smith Laboratories, Inc. Comprimés et trousses à libération contrôlée à base de niacine
EP0643965A1 (fr) * 1993-09-20 1995-03-22 Kos Pharmaceuticals, Inc. Compositions d'acide nicotinique pour le traitement de l'hyperlipidemie
WO1998039001A1 (fr) * 1997-03-06 1998-09-11 Kos Pharmaceuticals, Inc. Kit de depart contenant des compositions d'acide nicotinique
WO1999006046A1 (fr) * 1997-07-31 1999-02-11 Kos Pharmaceuticals, Inc. COMBINAISONS D'INHIBITEURS DE REDUCTASE HMG-CoA ET D'ACIDE NICOTINIQUE ET PROCEDES DE TRAITEMENT DE L'HYPERLIPIDEMIE
US6406715B1 (en) * 1993-09-20 2002-06-18 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique urinary metabolite profiles
WO2002067905A1 (fr) * 2001-02-27 2002-09-06 Kos Pharmaceuticals, Inc. Formulation pharmaceutique à libération lente
US20050118257A1 (en) * 1993-09-20 2005-06-02 Bova David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US20050148556A1 (en) * 2003-10-29 2005-07-07 Raif Tawakol Compositions and methods for increasing HDL and HDL-2b levels

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5126145A (en) * 1989-04-13 1992-06-30 Upsher Smith Laboratories Inc Controlled release tablet containing water soluble medicament
EP0577504A1 (fr) * 1992-06-29 1994-01-05 Upsher-Smith Laboratories, Inc. Comprimés et trousses à libération contrôlée à base de niacine
EP0643965A1 (fr) * 1993-09-20 1995-03-22 Kos Pharmaceuticals, Inc. Compositions d'acide nicotinique pour le traitement de l'hyperlipidemie
US6129930A (en) * 1993-09-20 2000-10-10 Bova; David J. Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night
US6406715B1 (en) * 1993-09-20 2002-06-18 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique urinary metabolite profiles
US20050118257A1 (en) * 1993-09-20 2005-06-02 Bova David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
WO1998039001A1 (fr) * 1997-03-06 1998-09-11 Kos Pharmaceuticals, Inc. Kit de depart contenant des compositions d'acide nicotinique
WO1999006046A1 (fr) * 1997-07-31 1999-02-11 Kos Pharmaceuticals, Inc. COMBINAISONS D'INHIBITEURS DE REDUCTASE HMG-CoA ET D'ACIDE NICOTINIQUE ET PROCEDES DE TRAITEMENT DE L'HYPERLIPIDEMIE
WO2002067905A1 (fr) * 2001-02-27 2002-09-06 Kos Pharmaceuticals, Inc. Formulation pharmaceutique à libération lente
US20050148556A1 (en) * 2003-10-29 2005-07-07 Raif Tawakol Compositions and methods for increasing HDL and HDL-2b levels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Dow Excipients: METHOCEL Products", INTERNET ARTICLE, 7 January 2007 (2007-01-07), XP002442270, Retrieved from the Internet <URL:http://web.archive.org/web/20070107033148/http://www.dow.com/dowexcipients/products/methocel.htm> [retrieved on 20070712] *

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