WO2007069827A1 - Composition pharmaceutique avec couche a liberation prolongee et couche a liberation rapide pour le traitement de l'hyperlipidemie et de l'arteriosclerose - Google Patents

Composition pharmaceutique avec couche a liberation prolongee et couche a liberation rapide pour le traitement de l'hyperlipidemie et de l'arteriosclerose Download PDF

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Publication number
WO2007069827A1
WO2007069827A1 PCT/KR2006/004738 KR2006004738W WO2007069827A1 WO 2007069827 A1 WO2007069827 A1 WO 2007069827A1 KR 2006004738 W KR2006004738 W KR 2006004738W WO 2007069827 A1 WO2007069827 A1 WO 2007069827A1
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Prior art keywords
pharmaceutical composition
gum
release layer
nicotinic acid
family
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PCT/KR2006/004738
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English (en)
Inventor
Hee Jong Shin
Min Hyo Ki
Jin Woo Lee
Byoung Su Kim
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2007069827A1 publication Critical patent/WO2007069827A1/fr

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    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to a pharmaceutical composition in the dosage form of tablet comprising a therapeutically amount of nicotinic acid and a nicotinic acid compound or mixtures thereof in a sustained release form and a therapeutically amount of a HMG- CoA reductase inhibitor in a fast release form which can optimally treat hyperlipidemia and arteriosclerosis by minimizing the interaction of two drugs, wherein the sustained release layer of nicotinic acid and a nicotinic acid compound or mixtures thereof is coated with a fast release layer of HMG-CoA reductase inhibitor or a separate layer of HMG-CoA reductase is embedded in the sustained release layer.
  • Low density lipoprotein carries cholesterol in the blood to the subendothelial spaces of blood vessel walls. It is believed that peroxidation of LDL-cholesterol within the subendothelial space of blood vessel walls leads to atherosclerosis plaque formation.
  • High density lipoprotein (HDL-cholesterol), on the other hand, is believed to counter plaque formation and delay or prevent the onset of cardiovascular disease and atherosclerotic symptoms.
  • Typical drugs for the treatment of hyperlipidemia or hypercholesterolemia include inhibitors of HMG-CoA reductase, the rate controlling enzyme in the biosynthetic pathway of cholesterol.
  • HMG-CoA reductase inhibitors include mevastatin, lovastatin, pitavastatin, velostatin, simvastatin, rivatatin, fluvastatin, atorvastatin and cerivastatin.
  • hypolipidemic agents include nicotinic acid, bile acid sequestrants such as cholestyramine, colestipol DEAE-Sephadex, probucol, and related compounds, as well as lipostabil, Eisai E-5050, imanixil, tetrahydrolipstatin, istigmastanylphospho- rylcholine, aminocyclodextrin, Ajinomoto AJ-814, melinamide, Sandoz 58-035, American Cyanamid CL- 277,082 and CL-283,546, ronitol, neomycin, p-aminosalicylic acid, aspirin, quaternary amine poly(diallyldimethylammonium chloride) and ionenes, poly(diallylmethylamine) derivatives, omega-3-fatty acids found in various fish oil supplements and fibric acid derivatives.
  • bile acid sequestrants such as cholestyramine, colestipol DEAE-Sephadex, probu
  • Nicotinic acid has been used for many years in the treatment of hyperlipidemia or hypercholesteremia. This compound has been known to exhibit the beneficial effects of reducing total cholesterol, very low density liproprotein (VLDL-cholesterol) and VLDL-cholesterol remnants, LDL-cholesterol, triglycerides and apolipoprotein, while increasing desirable HDL-cholesterol.
  • VLDL-cholesterol very low density liproprotein
  • VLDL-cholesterol very low density liproprotein
  • VLDL-cholesterol remnants LDL-cholesterol
  • triglycerides triglycerides
  • apolipoprotein apolipoprotein
  • a fast release nicotinic acid has conventionally been administered three times per day after meals, but cutaneous flushing often occurs in the hyperlipidemics to whom the nicotinic acid is administered.
  • Extended or sustained release formulations are designed to slowly release the active ingredient from the tablet or capsule, which allows a reduction in dosing frequency as compared to the typical dosing frequency associated with conventional or fast dosage forms.
  • the slow drug release reduces and prolongs blood levels of the drug and, thus, minimizes or lessens the cutaneous flushing side effects that are associated with conventional or fast release niacin products.
  • HMG-CoA reductase inhibitors have also been used for many years to treat hyperlipidemia. These compounds are known to exhibit beneficial effects of reducing total cholesterol and LDL-cholesterol in the human body, and elevating HDL-cholesterol levels in some individuals.
  • HMG-CoA reductase inhibitors Some combinations of HMG-CoA reductase inhibitors and nicotinic acid are known in the art in the treatment of hyperlipidemia.
  • European Patent No. 373,507 discloses a simple combination of HMG-CoA reduct ase inhibitor and HMG-CoA reductase inhibitor for treatment of hyperlipidemia and arteriosclerosis.
  • U.S. Patent No. 5,260,305 discloses a pharmaceutical composition including a
  • HMG-CoA reductase inhibitor pravastatin and nicotinic acid or nicotinic acid derivatives thereof such as acipimox, acipran, combination of nicotinic acid- N-oxide-2-t-butyl-4-cyclohexylphenyl ester.
  • WO 5817 discloses a pharmaceutical composition comprising HMG-CoA reductase inhibitor and p450 isoenzyme 3A4, its derivatives, inhibitors or substrates; this patent relates to a simple combination of HMG-CoA reductase inhibitor and niacin selected from p450 isoenzyme 3A4, its derivatives, inhibitors or substrates.
  • U.S. Patent No. 6,090,830 discloses a combination of microspheres formulated to co-deliver an immediate release HMG-CoA reductase inhibitor component plus a solubilizer and a sustained release nicotinic acid component.
  • Wo 3,103,640 discloses methods of manufacturing nanoparticle forms of HMG-
  • CoA reductase inhibitor to improve a low dissolution rate of HMG-CoA reductase inhibitor, requiring more complicated processes such as forming micro- or nano- particles and coating another controlled release film with a lower yield.
  • U.S. Patent No. 6,469,035 discloses methods of pretreating hyperlipidemic individuals with a flush inhibiting agent, including nonsteroidal anti-inflammatory agents, prior to the start of single daily dose nicotinic acid therapy to reduce flushing provoked by nicotinic acid.
  • the nicotinic acid may be administered alone or in combination with HMG-CoA reductase inhibitors.
  • U.S. Patent No. 4,053,975 and WO 9906035 disclose a combination of HMG-CoA reductase inhibitor and nicotinic acid, which would be taken once a day at night.
  • a bioavailability study of comparing Nicostatin, a new combination of Niaspan and lovastatin, made by Kos Pharmaceuticals and a single lovastin (Mevacor tablet) showed that C and AUC of max lovastatin contained in the combination product were in the range of about 75% and about 88% compared to those of a single lovastatin.
  • An object of the present invention is to provide a combination product of a HMG-
  • HMG-CoA reductase inhibitor and nicotinic acid, wherein the HMG-CoA reductase inhibitor is rapidly dissolved and absorbed into the body by minimizing the absorption associated with nicotinic acid.
  • the present invention is to provide a pharmaceutical composition in a tablet dosage form which can treat and prevent hyper- lipidemia and arteriosclerosis, wherein a coated bilayer tablet has a) one sustained release layer containing a therapeutically amount of nicotinic acid and a nicotinic acid compound or mixtures thereof, together with a sustained release polymer and b) another fast release layer containing a therapeutically amount of a HMG-CoA reductase inhibitor, a film- or layer- forming agent and a plasticizer which is coated on the outer layer of the sustained release layer or embedded on the sustained release layer as a separate layer; the fast release layer should necessarily contain a recrystallization inhibiting agent.
  • another object of the present invention is to provide a combination product containing the pharmaceutical composition, wherein a sustained release layer of the combination product provides extended plasma concentrations in water or a medium of physiological pH for at least 12 hours after administration, while a fast release layer has a dissolution profile of more than 80% within 30 minutes after administration, when contacted with water or in a medium of physiological pH.
  • the present invention is characterized by a pharmaceutical composition in a tablet dosage form for treatment and prevention of hyperlipidemia and arteriosclerosis, wherein a coated bilayer tablet has one sustained release layer containing a) a therapeutically amount of nicotinic acid and a nicotinic acid compound or mixtures thereof and b) one or more sustained release polymers, while a fast release layer, which is coated on the outer layer of the sustained release layer or embedded on the sustained release layer as a separate layer, containing c) one or more HMG-CoA reductase inhibitors as a therapeutically amount, d) one or more film- or layer-forming agents, e) one or more plasticizers and f) one or more recrystallization inhibiting agents that should necessarily be included in the fast release layer.
  • the sustained release layer containing nicotinic acid and a nicotinic acid compound and mixtures thereof provides extended plasma concentrations in water or a medium of physiological pH for at least 12 hours after administration, while the fast release layer containing a HMG-CoA reductase inhibitor has a dissolution profile of more than 80% within 30 minutes after administration, when contacted with water or in a medium of physiological pH.
  • An object of the present invention is to provide a pharmaceutical composition for oral solid dosage form comprising an extended release nicotinic acid, a derivative of nicotinic acid, a compound which is metabolized by the body to form nicotinic acid or any mixtures thereof, and a fast release HMG-CoA reductase inhibitor, pharmaceutical composition in oral administration for the treatment of hyperlipidemia and arteriosclerosis, without causing undesirable drug interaction between HMG-CoA reductase inhibitor and nicotinic acid.
  • the pharmaceutical composition is administered in amounts which are effective to alter or reduce serum lipids levels such as total cholesterol, VLDL-cholesterol, LDL- cholesterol, apolipoprotein and triglyceride levels, and to enhance or increase HDL- cholesterol levels.
  • the therapeutically effective dose of a HMG-CoA reductase inhibitor to alter serum lipid levels in individuals is in the range of from about 0.05 mg to about 160 mg, and preferably from about 0.05 to 80 mg, and more preferably from about 0.2 mg to about 40 mg.
  • a HMG-CoA reductase inhibitor to alter serum lipid levels in individuals is in the range of from about 0.05 mg to about 160 mg, and preferably from about 0.05 to 80 mg, and more preferably from about 0.2 mg to about 40 mg.
  • nicotinic acid its dose is in the range of from about 250 mg to about 3000 mg, and preferably from about 500 mg to about 2500 mg, and most preferably from about 1000 mg to about 2000 mg.
  • the HMG-CoA reductase inhibitor and nicotinic acid are employed together in the same oral dosage form or in separate oral dosage forms taken at the same or about the same time.
  • the dose may vary depending on a wide variety of parameters, including patients physiological needs.
  • the dose of nicotinic acid therefore, may be daily administered in increments of, for example, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg and 2500 mg.
  • the oral dosage form of the present invention may include the HMG-CoA reductase inhibitor in dosage amounts of, for example, 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg.
  • an oral solid dosage form such as tablets, may contain nicotinic acid, a nicotinic acid compound or any mixtures thereof and the HMG-CoA reductase inhibitor in dosage strengths of, for instance, 250 mg/2.5 mg, 500 mg/2.5 mg, 750 mg/2.5 mg, 1000 mg/2.5 mg, 2000 mg/2.5 mg, 250 mg/5 mg, 500 mg/5 mg, 750 mg/5 mg, 1000 mg/5 mg, 2000 mg/5 mg, 250 mg/7.5 mg, 500 mg/7.5 mg, 750 mg/7.5 mg, 1000 mg/7.5 mg, 2000 mg/7.5 mg, 250 mg/10 mg, 500 mg/10 mg, 750 mg/10 mg, 1000 mg/10 mg, 2000 mg/10 mg, 250 mg/20 mg, 500 mg/20 mg, 750 mg/20 mg, 1000 mg/20 mg, 2000 mg/20 mg, 250 mg/40 mg, 500 mg/ 40 mg, 750 mg/40 mg, 1000 mg/40 mg and 2000 mg/40 mg.
  • Nicotinic acid, a nicotinic acid compound or any mixtures thereof of the present invention specifically include, but are not limited to the following: nicotinic acid, nicotinyl alcohol tartrate, D-glucitol hexanicotinate, aluminium nicotinate, niceritrol , D-L-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N- methyl-2-pyridine-8-carboxamide, N-methyl-nicotinamide, N- ribosyl-2-pyridone-5-carboxide, N-methyl-4-pyridone-5-carboxamide, bradilian, sorbinicate, hexanicite, ronitol , and esters of nicotinic acid such as lower alcohol esters like methyl,
  • the sustained release layer of nicotinic acid, a nicotinic acid compound or mixtures thereof of the present invention is formulated by mixing with a binder and binding solution or otherwise, the mixtures of the active ingredient and a sustained release polymer is formulated to ensure the sustained release profile. If the pharmaceutical composition of the present invention is orally administered to patients, the active ingredient (i.e., nicotinic acid, a nicotinic acid compound or mixtures thereof) is released over time via the sustained release polymer.
  • the sustained release polymer of the present invention allows a slower release of the active ingredient for at least 6 hours, preferably for more than 12 hours, in a manner to reduce the side effects of a rapid plasma concentration when the drug content is rapidly released and to prolong the onset of drug. More specifically, the release rate of the active ingredient (nicotinic acid and a nicotinic acid compound or mixtures thereof) may be sustained by about 80% or more.
  • sustained release polymer examples include, but not limited to cellulose derivatives, such as hydroxypropyl- methylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hy- droxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydrox- yethylethylcellulose, hydroxypropylethylcellulose, alkyl hydroxypropylmethyl- cellulose; polysaccharide family, such as corn starch, potato starch, alpha starch and hydroxyethyl starch as its derivative, dextrin and dextran as its derivative, mal- todextrin, polydextrose, alginic acid alkali metal salt as a family of alginic acid; gum family, such as guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, casein, tara gum, tama
  • the sustained release polymer may be employed within the range of from about 1% to about 70% by weight, preferably from about 10% to about 50% by weight per hundred parts by weight of the tablet or formulation.
  • the chemical composition of the sustained release polymer will ensure a sustained time release.
  • the sustained release layer of nicotinic acid and a nicotinic acid compound or any mixtures thereof may include one or more pharmaceutically acceptable diluents, binders, disintegrants, colorants, preservatives, foaming agents and lubricants, as well as any excipients having such multiple functions.
  • the sustained release layer of the present invention may include, but are not limited to, one or more diluents, such as lactose, dextrose, noncrystalline cellulose and starch; one or more binders, such as hydroxypropylcellulose (low molecular weight) and povidone; one or more disintegrants, such as croscarmellose sodium, sodium starch glycolate, polyvinyl pyrrolidone for cross-linked, alpha starch and low-substituted hy- droxypropyl cellulose; one or more colorants, such as water-soluble and tar pigment; one or more preservatives, such as benzoic acid, methylparaben, ethylparaben, propylparaben; one or more foaming agents, such as calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium glycine carbonate; one or more lubricants, such as stearic acid, magnesium stearate, talc,
  • the sustained release composition containing nicotinic acid and/or nicotinic acid compounds are preferably coated with an HMG-CoA reductase inhibitor for fast release following oral administration.
  • the sustained release composition containing nicotinic acid and a nicotinic acid compound or mixtures thereof is coated with a fast release HMG-CoA reductase inhibitor, or has a separate layer; provided, however, that the fast release layer is directly coated on the sustained release layer containing nicotinic acid and a nicotinic acid compound or mixtures thereof, or its separate layer is provided along with a drug-free protective film of one more layers; the internal or outer part of the fast release layer is formulated by a common method.
  • HMG-CoA reductase inhibitors of the present invention include, but are not limited to mevastatin, lovastatin, pitavastatin, velostatin, simvastatin, rivatatin, fluvastatin, atorvastatin and cerivastatin.
  • a film- or layer-forming agent is employed to form a coating film of a fast release layer containing a HMG-CoA reductase inhibitor or a separate layer on the sustained release layer containing nicotinic acid and a nicotinic acid compound or mixtures thereof.
  • the film- or layer-forming agent containing the HMG-CoA reductase inhibitor allows a combination of two components through its attachment to the sustained release layer containing nicotinic acid and a nicotinic acid compound or mixtures thereof, thus forming a coated film or separate layer as above.
  • film- or layer- forming agents include, but are not limited to cellulose family, such as noncrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethyl- cellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylethyl- cellulose, hydroxypropylethylcellulose, alkyl hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate and cellulose acetate phthalate; polysaccharide family, such as corn starch, potato starch and alpha starch and its derivative hydroxyethyl starch, dextrin and its derivative dextran, maltodextrin and polydextrose; gum family, such as guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum
  • a recrystallization inhibiting agent is employed for better fast release profile of a HMG-CoA reductase inhibitor.
  • HMG-CoA reductase inhibitors are present as poorly insoluble crystalline form in water, the use of a film- or layer-forming agent is very important for dispersing the drugs and preventing their recrystallization accompanied by the manufacturing process or storage.
  • the change or precipitation of a water-insoluble drug into a crystalline form may occur gradually for a prolonged period of time, and the newly formed crystalline form of drug has a low solubility to water, thus preventing a rapid dissolution and causing a lower dissolution rate.
  • the HMG-CoA reductase inhibitor is dissolved in a film- or layer-forming agent and an organic solvent to form a coating film or separate layer but after evaporating the solvent, the drug precipitated from the coating film or separate layer is poorly soluble in water, making it difficult to achieve a fast release profile of drug due to a low solubility.
  • the recrystallization of a drug will result in the reduction of its thermodynamic activity, thus leading to reduced solubility of the drug and poor solubility of a pharmaceutical composition during a long-term storage.
  • the formation of a coating film of a fast release layer containing a HMG-CoA reductase inhibitor or a separate layer on the sustained release layer through the mixing or dissolution of a recrystallization inhibiting agent and the HMG-CoA reductase inhibitor makes it possible to achieve a more rapid dissolution of the HMG-CoA reductase inhibitor, which cannot be achieved by the conventional composition of a coat film or separate layer.
  • the HMG-CoA reductase inhibitor is present within a coating film of the fast release layer or separate layer using a film- or layer- forming agent, and as the recrystallization process progresses due to formation of crystal cores from the attractive force of drug particles, the solubility of drug and its dissolution rate will decrease.
  • the recrystallization inhibiting agent acts on the particles of the HMG-CoA reductase inhibitor within a coating film of the fast release layer or separate layer that may prevent the formation of crystal cores between drug particles, thus resulting in better solubility and fast release profile of drug within a coating film of the fast release layer or separate layer.
  • recrystallization inhibiting agents include, but not limited to vinyl pyrrolidone family, such as polyvinyl pyrrolidone, crospovidone, polyvinyl pyrrolidone/vinylacetate copolymer; dextrin derivatives, such as cyclodextrin, dimethyl cyclodextrin, hydroxyethyl cyclodextrin, hydroxypropyl cyclodextrin and trimethyl cyclodextrin; alkylene oxide family, such as poloxamer, polyethylene glycol and polyethylene oxide; acrylate family, such as polymethacrylate and its derivatives (brandnaem: Eudragit series) and polysaccharide family, such as alginic acid and its alkali metal salt, and polyvinyl acetate.
  • vinyl pyrrolidone family such as polyvinyl pyrrolidone, crospovidone, polyvinyl pyrrolidone/vinylacetate copoly
  • an exemplary amount of the recrystallization inhibiting agent is in an amount ranging from about 0.01 to about 30% by weight per tablet, preferably from about 0.5 to about 10% by weight.
  • a plasticizer is employed for forming a coating film or separate layer of the HMG-CoA reductase inhibitor and for its fast release profile.
  • the plasticizer used for the present invention is a substance that can provide plasticity, tension and adhesiveness to a coating film or separate layer of the HMG- CoA reductase inhibitor, thus supporting the formation of a coating film and providing a flexibility to the film.
  • the film- or layer-forming agent is liable to form a hard mass in a three-dimensional shape, when a coating film or separate layer of the HMG-CoA reductase inhibitor is formed.
  • a plasticizer can remove such hard mass and provide a plasticity to the formation of a coating film and separate layer.
  • the plasticizer allows more homogeneous arrangement of the HMG-CoA reductase inhibitor within a coating film and separate layer, together with the film- or layer- forming agent, thus ensuring the dissolution or separation of a coating film and separate layer within a short period that will contribute to better rapid release profile of the HMG-CoA reductase inhibitor.
  • plasticizers include, but are not limited to, poly glyceryl fatty acid esters, polyoxyethylene glyceryl fatty acid esters, sorbitan fatty acid esters, poly- oxyethylene sorbitol fatty acid esters, polyethylene glycol and polyethylene glycol fatty acid esters, polyoxyethylene castor oils, polyoxyethylene alkyl ethers, polyoxyethylene phytosterols, polyoxyethylene alkyl phenyl ethers, polyoxyethylene poly- oxypropylene alkyl ethers, polyoxyethylene lanolines, polyoxyethylene alkyl ether phosphates, propylene glycol and propylene glycol fatty acids, glycerol fatty acid esters, fatty acid macrogol glycerides, glyceryl monolinoleate, glyceryl monooleate, diethylene glycol monoethyl ether, benzylbenzoate, chlorobutanol, dibutyl sebacate, die
  • the rapid release coating film or separate layer of the HMG-CoA reductase inhibitor may include one or more pharmaceutically acceptable disintegration enhancing agents, anti-oxidants, dispersants, polishing agents, sunscreen agents and colorants, as well as any excipients having such multiple functions.
  • additional formulating agents may be used as follows: (1) one or more disintegration enhancing agents may be selected from the group comprising Primojel and Avicel; (2) one or more anti-oxidants may be selected from the group comprising ascorbic acid, butylated hydroxyanisole, citric acid, tocopherol and its derivative and compound; (3) one or more dispersants may be selected from the group comprising talc, precipitated calcium carbonate, magnesium stearate, calcium sulfate, sugar, microsilica and calcium phosphate, starches; (4) one or polishing agents may be selected from the group comprising carnauba wax and bees wax, and (5) one or more colorants may be selected from the group comprising titanium oxide, zinc oxide, soluble and tar pigment.
  • composition is prepared, but is not limited to the following process.
  • a mixture of nicotinic acid and a nicotinic acid compound or mixtures thereof and a sustained release polymer is passed through a 30 mesh size screen or more for more homogenous mixing.
  • This mixture is formulated by wet granulation or compression molding using a tabletting machine. If necessary, one or more diluents, disintegrants, pigments, colorants, preservatives, foaming agents or lubricants may be additionally employed.
  • a HMG-CoA reductase inhibitor is immersed in an appropriate organic solvent for complete mixing and with the addition of a film- or layer- forming agent and a recrystallization inhibiting agent, the reacting mixture is dissolved and dispersed homogenously.
  • a costing solution may be prepared by adding one more plasticizers, disintegration enhancing agents, antioxidants, dispersants, polishing agents, sunscreen agents and colorants.
  • the coating solution, so prepared is sprayed to a sustained release tablet containing nicotinic acid and a nicotinic acid compound or mixtures thereof after evaporating a solvent, adding a layer containing a fixed amount of HMG-CoA reductase inhibitor per tablet, thus making a pharmaceutical composition of the present invention.
  • the rapid release layer may have a drug-free protective film of one more layers.
  • the sustained release polymer of the pharmaceutical composition allows a slower release of nicotinic acid and a nicotinic acid compound or mixtures thereof for at least 6 hours, preferably for more than 12 hours, while a fast release layer has a dissolution profile of more than 80% within 30 minutes after administration, preferably within 15 minutes, when contacted with water or in a medium of physiological pH.
  • the HMG- CoA reductase inhibitor that is rapidly released from the pharmaceutical composition of the present invention may avoid the drug interaction with nicotinic acid and a nicotinic acid compound or mixtures thereof in the gastrointestinal tract and address the reduced bioavailability.
  • the pharmaceutical composition of the present invention should be prepared in such a manner that the dissolution rate of the HMG-CoA reductase inhibitor was more than 12 times faster than nicotinic acid, preferably more than 24 times, and most preferably more than 36 times, until the two active ingredients were released by 80%.
  • a pharmaceutical composition comprising a HMG-CoA reductase inhibitor and nicotinic acid is provided in such a manner that the
  • HMG-CoA reductase inhibitor is rapidly absorbed in the body, minimizing an undesired drug interaction associated with nicotinic acid and optimizing the therapeutic effect of the composition in the treatment and prevention of hyperlipidemia and arteriosclerosis.
  • the pharmaceutical composition of the present invention may not only exhibit more optimal therapeutic effect in reducing LDL-cholesterol levels and enhancing HDL- cholesterol levels than the conventional combination product of a HMG-CoA reductase inhibitor and nicotinic acid, but also avoid the drug interaction the conventional combination product has encountered.
  • Fig. 1 shows the dissolution profile of nicotinic acid obtained with a sustained release nicotinic acid including sustained release polymers of Examples 2, 3 and 4.
  • Fig. 2 shows the dissolution profile of simvastatin released from a fast release simvastatin film or separate layer of Examples 6, 13, 15, 17 and 19.
  • Fig. 3 shows the dissolution profile of simvastatin released from a combination of a sustained release nicotinic acid layer of Example 27 and a fast release simvastatin layer of Comparative example 1.
  • Fig. 1 shows the dissolution profile of nicotinic acid obtained with a sustained release nicotinic acid including sustained release polymers of Examples 2, 3 and 4.
  • Fig. 2 shows the dissolution profile of simvastatin released from a fast release simvastatin film or separate layer of Examples 6, 13, 15, 17 and 19.
  • Fig. 3 shows the dissolution profile of simvastatin released from a combination of a sustained release nicotinic acid layer of
  • FIG. 4 shows the dissolution profile of simvastatin released from a combination of a sustained release nicotinic acid layer of Examples 41, 43 and a fast release simvastatin layer of Comparative example 2.
  • Fig. 5 shows the dissolution profile of nicotinic acid and simvastatin released from a combination of a sustained release nicotinic acid layer and a fast release simvastatin layer of Examples 44, 45.
  • Fig. 6 shows the dissolution profile of atorvastatin released from a combination of a sustained release nicotinic acid layer of Examples 50, 51 and a fast release simvastatin layer of Comparative example 3.
  • compositions of Examples 1-4 (Unit: mg)
  • Example 1 Example 2 Example 3 J ⁇ xamj3le 4_
  • the volumetric unit of organic solvent is mL
  • a coating solution (I) was prepared using simvastatin, hydroxypropylmethylcellulose 2910 as a film- or layer- forming agent, copovidone/povidone/Eudragit EPO as a recrystallization inhibiting agent and polyethylene glycol 6000, citric acid triethyl/polysorbate 80/sorbitol as a plasticizer in the presence of ethanol and dichloromethane as a co-solvent.
  • the coating solution (I) was passed through a #100 mesh size screen. Core tablets, so formed by Example 2, were coated with the coating solution (I).
  • a coating solution (I) for a drug-free protective film was prepared using hydroxypropylmethylcellulose 2910 as a film- or layer- forming agent, polyethylene glycol 6000 as a plasticizer and titanium oxide as a colorant in the presence of ethanol and dichloromethane as a co-solvent.
  • a coating solution (II) was prepared using simvastatin, hydroxypropylmethylcellulose 2910 as a film- or layer- forming agent, copovidone/Eudragit EPO as a recrystallization inhibiting agent, polyethylene glycol 6000/citric acid triethyl as a plasticizer and talc as an excipient in the presence of a co-solvent of ethanol and dichloromethane.
  • the two coating solutions (I, II) were passed through a #100 mesh size screen. Core tablets, so formed by Example 3, were initially coated with the coating solution (I) and subsequently with the coating solution (II).
  • a coating solution (I) for a drug-free protective film was prepared using hydroxypropylmethylcellulose 2910 as a film- or layer-forming agent, polyethylene glycol 6000 as a plasticizer and titanium oxide as a colorant in the presence of ethanol and dichloromethane as a co-solvent.
  • a coating solution (II) was prepared using simvastatin, hydroxypropylmethylcellulose 2910 as a film- or layer-forming agent, copovidone/povidone/Eudragit EPO as a recrystallization inhibiting agent and citric acid triethyl/sorbitol as a plasticizer, butylated hydroxyanisole/citric acid as an anti-oxidant and talc as an excipient in the presence of ethanol and dichloromethane as a co-solvent.
  • the two coating solutions (I, II) were passed through a #100 mesh size screen. Core tablets, so formed by Example 2, were initially coated with the coating solution (I) and sub- sequently with the coating solution (II). After being dried for a given time, tablets were re-coated with the coating solution (I) in increments of 3 mg per tablet.
  • a coating solution (I) was prepared using simvastatin, hydroxypropylmethylcellulose 2910/hydroxyethylcellulose as a film- or layer-forming agent, copovidone/povidone/Eudragit EPO as a recrys- tallization inhibiting agent, polyethylene glycol 6000/citric acid triethyl as a plasticizer, butylated hydroxyanisole/citric acid as an anti-oxidant and talc/titanium oxide as an excipient in the presence of ethanol and dichloromethane as a co-solvent.
  • a coating solution (I) was prepared using simvastatin, hydroxypropylmethylcellulose 2910/hydroxyethylcellulose as a film- or layer-forming agent, copovidone/povidone/Eudragit EPO as a recrys- tallization inhibiting agent, polyethylene glycol 6000/citric acid triethyl/sodium lauryl sulfate/docusate sodium as a plasticizerbutylated hydroxyanisole as an anti-oxidant and titanium oxide as a colorant in the presence of ethanol and dichloromethane as a co- solvent.
  • the coating solution (I) were passed through a #100 mesh size screen. Core tablets, so formed by Example 3, were coated with the coating solution (I).
  • a coating solution (I) was prepared using atorvastatin, hydroxypropylmethylcellulose 2910/hydroxyethylcellulose as a film- or layer- forming agent, copovidone/ povidone/Eudragit EPO as a recrystallization inhibiting agent, polyethylene glycol 6000/citric acid triethyl/sodium lauryl sulfate/docusate sodium as a plasticizer, butylated hydroxyanisole as an anti-oxidant and titanium oxide as a colorant in the presence of ethanol and dichloromethane as a co-solvent.
  • the coating solution (I) were passed through a #100 mesh size screen. Core tablets, so formed by Example 2, were coated with the coating solution (I).
  • a coating solution (I) was prepared using simvastatin, hydroxypropylmethylcellulose 2901 as a film- or layer-forming agent, polyethylene glycol 6000/sodium lauryl sulfate/docusate sodium as a plasticizer, butylated hydroxyanisole as an anti-oxidant and titanium oxide as a colorant in the presence of ethanol and dichloromethane as a co-solvent.
  • the coating solution (I) were passed through a #100 mesh size screen. Core tablets, so formed by Example 2, were coated with the coating solution (I).
  • Comparative example 2 were performed to determine its dissolution profile.
  • the dissolution rates of nicotinic acid and simvastatin were calculated, as illustrated in Figs. 4 and 5.
  • the dissolution rate of simvastatin was at least 36 times faster than nicotinic acid at the same temperature and rotation number of a dissolution device until the two active ingredients were released by 80%.
  • Comparative example 3 were performed to determine its dissolution profile.
  • the dissolution rates of nicotinic acid and simvastatin were calculated, as illustrated in Fig. 6.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant une dose thérapeutique d'acide nicotinique et d'un composé d'acide nicotinique ou des mélanges de ces derniers sous une forme à libération prolongée, et un dose thérapeutique d'inhibiteur de HMG-CoA réductase sous une forme à libération rapide qui permettent d'optimiser le traitement de l'hyperlipidémie et de l'artériosclérose en réduisant l'interaction des deux médicaments. Cette composition pharmaceutique se présente sous la forme d'un comprimé à double couche, soit (a) une couche à libération prolongée contenant de l'acide nicotinique et un composé d'acide nicotinique ou des mélanges de ces derniers associés à un polymère à libération prolongée et (b) une autre couche à libération rapide contenant un inhibiteur de HMG-CoA réductase, un agent filmogène ou formant une couche, un inhibiteur de recristallisation et un plastifiant. Ladite composition permet de minimiser les interactions entre les deux médicaments via son profil à libération contrôlée et d'optimiser le traitement optimal de l'hyperlipidémie et l'artériosclérose.
PCT/KR2006/004738 2005-12-14 2006-11-13 Composition pharmaceutique avec couche a liberation prolongee et couche a liberation rapide pour le traitement de l'hyperlipidemie et de l'arteriosclerose WO2007069827A1 (fr)

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Cited By (7)

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WO2008087010A1 (fr) * 2007-01-19 2008-07-24 Medice Arzneimittel Puetter Gmbh & Co. Kg Utilisation de nicotinamide pour le traitement et/ou la prévention de l'artériosclérose
WO2009016577A2 (fr) * 2007-07-27 2009-02-05 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant de l'atorvastatine et de la niacine
WO2011154755A1 (fr) 2010-06-08 2011-12-15 Nanoform Cardiovascular Therapeutics Ltd. Atorvastatine nanostructurée, ses sels pharmaceutiquement acceptables et des compositions de ceux-ci, procédé pour leur préparation et compositions pharmaceutiques les contenant
RU2468789C1 (ru) * 2011-05-04 2012-12-10 Федеральное государственное бюджетное учреждение науки Иркутский институт химии им. А.Е. Фаворского Сибирского отделения Российской академии наук (ИрИХ СО РАН) Средство для профилактики и лечения атеросклероза
US9216160B2 (en) 2011-10-05 2015-12-22 Jeffrey M. Golini Choline composition
CN111303907A (zh) * 2020-04-13 2020-06-19 曲阜师范大学 一种防尘固沙环保液体地膜材料的制备方法
CN112739383A (zh) * 2018-09-19 2021-04-30 埃斯普投资有限公司 过氧化物稳定的聚合物组合物及其制备方法和应用

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KR101052947B1 (ko) * 2008-07-22 2011-07-29 한국콜마 주식회사 아젤라스틴 액상 제제
KR102380498B1 (ko) * 2021-02-24 2022-04-01 주식회사 청안오가닉스 건강기능식품에 있어서 유효성분의 지속적인 방출을 제어할 수 있는 서방형 정제를 제조하기 위한 조성물

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008087010A1 (fr) * 2007-01-19 2008-07-24 Medice Arzneimittel Puetter Gmbh & Co. Kg Utilisation de nicotinamide pour le traitement et/ou la prévention de l'artériosclérose
DE102007003524A1 (de) * 2007-01-19 2008-09-04 MEDICE Arzneimittel Pütter GmbH & Co. KG Arzneimittel zur Behandlung und/oder Prävention von Arteriosklerose
WO2009016577A2 (fr) * 2007-07-27 2009-02-05 Ranbaxy Laboratories Limited Composition pharmaceutique comprenant de l'atorvastatine et de la niacine
WO2009016577A3 (fr) * 2007-07-27 2009-03-26 Ranbaxy Lab Ltd Composition pharmaceutique comprenant de l'atorvastatine et de la niacine
WO2011154755A1 (fr) 2010-06-08 2011-12-15 Nanoform Cardiovascular Therapeutics Ltd. Atorvastatine nanostructurée, ses sels pharmaceutiquement acceptables et des compositions de ceux-ci, procédé pour leur préparation et compositions pharmaceutiques les contenant
RU2468789C1 (ru) * 2011-05-04 2012-12-10 Федеральное государственное бюджетное учреждение науки Иркутский институт химии им. А.Е. Фаворского Сибирского отделения Российской академии наук (ИрИХ СО РАН) Средство для профилактики и лечения атеросклероза
US9216160B2 (en) 2011-10-05 2015-12-22 Jeffrey M. Golini Choline composition
CN112739383A (zh) * 2018-09-19 2021-04-30 埃斯普投资有限公司 过氧化物稳定的聚合物组合物及其制备方法和应用
CN112739383B (zh) * 2018-09-19 2024-03-15 埃斯普投资有限公司 过氧化物稳定的聚合物组合物及其制备方法和应用
CN111303907A (zh) * 2020-04-13 2020-06-19 曲阜师范大学 一种防尘固沙环保液体地膜材料的制备方法

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