WO2007069827A1 - Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis - Google Patents
Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis Download PDFInfo
- 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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- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- gum
- release layer
- nicotinic acid
- family
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- 208000031226 Hyperlipidaemia Diseases 0.000 title claims abstract description 19
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- 210000004369 blood Anatomy 0.000 description 1
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- 230000036765 blood level Effects 0.000 description 1
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- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
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- 235000021323 fish oil Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 229920013819 hydroxyethyl ethylcellulose Polymers 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 229950010293 imanixil Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229950008446 melinamide Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- RKXDBBSILRGMLE-UHFFFAOYSA-N methyl 3-ethyl-6-propan-2-ylazulene-1-carboxylate Chemical compound C1=CC(C(C)C)=CC=C2C(CC)=CC(C(=O)OC)=C21 RKXDBBSILRGMLE-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
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- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-M pravastatin(1-) Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-M 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- QWSZRRAAFHGKCH-UHFFFAOYSA-M sodium;hexane-1-sulfonate Chemical compound [Na+].CCCCCCS([O-])(=O)=O QWSZRRAAFHGKCH-UHFFFAOYSA-M 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
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
-
- 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.
Abstract
The present invention provides a pharmaceutical composition 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. The pharmaceutical composition of the present invention comprising a coated two- layer tablet a) one sustained release layer containing nicotinic acid and a nicotinic acid compound or mixtures thereof, together with a sustained release polymer and b) another fast release layer containing a HMG-CoA reductase inhibitor, a film- or layer- forming agent, a re- crystallization inhibitor and a plasticizer, can minimize the interaction of the two drugs via controlled release profile and treat optimally hyperlipidemia and arteriosclerosis.
Description
Description
PHARMACEUTICAL COMPOSITION WITH EXTENDED RELEASE LAYER AND FAST RELEASE LAYER FOR TREATMENT OF HYPERLIPIDEMIA AND ARTERIOSCLEROSIS Technical Field
[1] 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.
[2]
Background Art
[3] Hyperlipidemia or an elevation in serum low density lipoprotein-cholesterol and total cholesterol is closely associated with an increase incidence of cardiovascular disease and atherosclerosis.
[4] It is known that the likelihood of cardiovascular disease can be decreased, if the serum lipids, and in particular low density lipoprotein-cholesterol (LDL-cholesterol), can be reduced.
[5] It is also well known that the progression of atherosclerosis can be retarded or the regression of atherosclerosis can be induced if serum lipids can be lowered.
[6] In such cases, individuals diagnosed with hyperlipidemia should consider lipid- lowering therapy for purposes of reducing their risk of cardiovascular disease.
[7] People with hyperlipidemia also have elevated triglyceride levels. It is known that a reduction in elevated triglycerides can result in the secondary lowering of cholesterol. These individuals should also consider lipid-lowering therapy to reduce their elevated triglycerides for purposes of decreasing their incidence of atherosclerosis and coronary artery disease.
[8] 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.
[9] 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.
[10] In the past, there have been numerous methods proposed for reducing elevated cholesterol levels and for increasing HDL-cholesterol levels for the purpose of treating hyperlipidemia and arteriosclerosis or cardiovascular diseases.
[11] 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. Examples of HMG-CoA reductase inhibitors include mevastatin, lovastatin, pitavastatin, velostatin, simvastatin, rivatatin, fluvastatin, atorvastatin and cerivastatin.
[12] Other 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.
[13] 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.
[14] 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.
[15] In order to avoid or alleviate the cutaneous flushing resulting from nicotinic acid therapy, a number of agents have been suggested. Another method of avoiding or reducing the side effects associated with fast release niacin is the use of extended or sustained release formulations. 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.
[16] 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.
[17] Some combinations of HMG-CoA reductase inhibitors and nicotinic acid are known in the art in the treatment of hyperlipidemia.
[18] 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.
[19] 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.
[20] 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.
[21] 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.
[22] 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.
[23] 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.
[24] 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. According to the Clinical Pharmacology and Biopharmaceutics Review issue submitted to the U.S. Food and Drug Administration, 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.
[25] The inventors have learnt from the comparative trial that there were differences of bioavailability in terms of absorption and metabolism between a new combination of Niaspan/lovastatin and a single lovastatin, because a single lovastatin had a fast
dissolution profile but lovastatin in the combination product had a 1-hour dissolution profile.
[26] To address the above problem, the inventors have endeavored to develop a new combination product of HMG-CoA reductase inhibitor and nicotinic acid that can minimize the drug interaction associated with nicotinic acid, thus ensuring a rapid release and absorption of HMG-CoA reductase inhibitor in the body. As a consequence the inventors consummated this invention.
[27]
Disclosure of Invention Technical Problem
[28] An object of the present invention is to provide a combination product of a 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.
[29]
Technical Solution
[30] To achieve the aforementioned objective, 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.
[31] Further, 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.
[32] The present invention is described in more detail as set forth hereunder.
[33] 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.
[34] 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.
[35] 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.
[36] For oral administration, a satisfactory result may be obtained employing a HMG-
CoA reductase inhibitor in combination with nicotinic acid. For example, 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. For 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.
[37] Thus, and in accordance with the present invention, 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.
[38] 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, ethyl, propyl or butyl esters. Each of such derivatives or compounds will be collectively referred to hereinabove by "nicotinic acid compound."
[39] Further, 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.
[40] 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.
[41] Examples of the sustained release polymer which may be suitable for the present invention 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, tamarind gum, tragacanth gum and ghatti gum; peptide series, such as gelatin, collagen, protamine and zein; acrylic acid series carbomer, polyacrylamide, and other materials (e.g., polyvinylacetal diethy- laminoacetate, glucomannan, glucosamine, arabinogalactane, furcelleran, pullulan, polyurethane, chitosan, chitin, agar, pectin and carrageenan.
[42] 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.
[43] According to the present invention, 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.
[44] 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, hard silicon dioxide, sucrose fatty acid ester and glyceryl behenate.
[45] Also in accordance with the present invention, 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.
[46] According to the present invention, 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.
[47] The HMG-CoA reductase inhibitors of the present invention include, but are not limited to mevastatin, lovastatin, pitavastatin, velostatin, simvastatin, rivatatin,
fluvastatin, atorvastatin and cerivastatin.
[48] According to this invention, 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.
[49] Specific examples of 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, casein, tara gum, tamarind gum, tragacanth gum and ghatti gum; peptide family, such as gelatin, collagen, protamine and zein; acrylic acid family, such as carbomer and polyacrylamidewax family, such as carnauba wax and beeswax; carbohydrate family, such as sucrose, liquid sucrose, lactose and polyvinylacetal diethy- laminoacetate and other materials (e.g., polyurethane, chitosan, chitin, agar, pectin, carrageenan and shellac). According to the present invention, an exemplary amount of the film- or layer- forming agent is in an amount ranging from about 0.01 to about 50% by weight per tablet, preferably from about 0.5 to about 10% by weight.
[50] According to the present invention, a recrystallization inhibiting agent is employed for better fast release profile of a HMG-CoA reductase inhibitor. As all of HMG-CoA reductase inhibitors is 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.
[51] Furthermore, under the circumstances where there is no method available to effectively prevent the formation of crystalline form of drug, even excessive use of a common surfactant 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, as known in the art, has a distinct limitedness to increase the dissolution rate of the HMG-CoA reductase inhibitor. More specifically, water-insoluble drugs are dissolved in an organic solvent with better solubility but after evaporating the solvent, they are liable to be recrystallized and poorly soluble in water. 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.
[52] According to the present invention, 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.
[53] 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.
[54] Specific examples of 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. According to the present invention, 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.
[55] According to the present invention, 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. By contrast, a plasticizer can remove such hard mass and provide a plasticity to the formation of a coating film and separate layer. Further, 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.
[56] Specific examples of 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, diethyl phthalate, glycerin, mineral oil and lanolin alcohol, petroleum and lanolin alcohol, triacetin and triethyl citrate, sodium lauryl sulfate, docusate sodium, sorbitol and mannitol.
[57] Further, according to the present invention, 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.
[58] According to the present invention, 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.
[59] The pharmaceutical composition is prepared, but is not limited to the following process.
[60] Firstly, 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. Separately, 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. If necessary, 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. Hence, the rapid release layer may have a drug-free protective film of one more layers.
[61] According to the present invention, 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. By achieving the opposite release properties, 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. Considering the opposite release rate into due consideration, 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%.
Advantageous Effects
[62] According to the present invention, 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. [63] 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. [64]
Brief Description of the Drawings [65] 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. [66] [67] 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. [68] [69] 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. [70] [71] 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. [72] [73] 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. [74] [75] 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. [76]
Best Mode for Carrying Out the Invention [77] This invention will now be described by reference to the following examples and experimental examples which are merely illustrative and which are not to be construed
as a limitation of the scope of this invention.
[78] [79] Examples 1-4 [80] A number of sustained release tablets comprising nicotinic acid and a nicotinic acid compound and mixtures thereof were prepared. Each component and content of the compositions was indicated in Table 1.
[81] [82] Table 1
Pharmaceutical compositions of Examples 1-4 (Unit: mg)
Example 1 Example 2 Example 3 JΞxamj3le 4_
Nicotinic acid 375 500 750 1000
HPMC 2208 97.5 130 130 130
Polyethylene oxide 30 40
Silicone dioxide 15 20 20 _20_
I Sodium bicarbonate 11.25 15 15 j Stearic acsd 1 1 « 15 15 j Total J MU .._ _. 720 970 1220
[83] [84] Except for stearic acid as a lubricant, all components were mixed together. The resulting mixture was passed through a #30 mesh size screen. Thereafter, stearic acid was added to the mixtures and mixed. The resulting mixture was then compressed into tablets.
[85] [86] Examples 5-19 [87] Based on the different compositions described in Tables 2, 3 and 4, a film was prepared in such a manner that simvastatin, hydroxypropylmethyl cellulos 2910 as a film- or layer-forming agent and polyethylene glycol 6000 as a plasticizer in a co- solvent of ethanol and dichloromethane; and then, povidone, copovidone, poloxamer, Eudragit and HP-β-cyclodextrin were added to the solution. Each solution of 5 mL was injected to Petri dishes in diameter of 4cm. The solvent was evaporated under reduced pressure at 6O0C.
[88] [89] Table
Pharmaceutical compositions of Examples 5-19 (Unit' mg)
[90] Table 3
Pharmaceutical compositions of Examples 10-14 (Unit: mg)
[91] Table 4
Pharmaceutical compositions of Examples 15-19 (Unit: mg)
The volumetric unit of organic solvent is mL
[92] [93] Examples 20-25 [94] Based on the different compositions described in Table 5, 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).
[95] [96] Table 5
Pharmaceutical compositions of Examples 20-25 (Unit, mg)
fcxample Example Fx^mple I Erømplθ Example E^ar-p'e 2C 23 __ _25_ uore tab ! fcxamplβ I IAS /20 720 7?0 720
Siiπvεstatin 20 20 20 20 20 _ 20_ _
HPMC 2910 10 30 20 20 20
Gopomdoπβ 20 30 30
Eudragit EPO 30
30
PEG 6000
TEC 7 5 10 10 10
Polysorbate 7 5 10 10 10 80
Sorbitol 10 20 20 20
Total 789 780 825 830 830 830
[97] [98] Examples 26-31 [99] Based on the different compositions described in Table 6, 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.
[100] Separately, 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).
[101] [102] Table 6
Pharmaceutical compositions of Examples 26-31 (Unit: mg)
[103] [104] Examples 32-34 [105] Based on the different compositions described in Table 7, 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.
[106] Separately, 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.
[107] [108] Table 7
Pharmaceutical compositions of Examples 32-34 (Unit: mg)
[109] [HO] Examples 35-40 [111] Based on the different compositions described in Table 8, 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.
[112] 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).
[113] [114] Table 8
Pharmaceutical compositions of Examples 35-40 (Unit' mg)
Example Example Example Example Example Example 35 36 37 38 39 40
Core tab Example 2 720 720 720 720 720 720
Simvastatin 20 20 20 20 20 20
HPMC 2910 10 96 10 96
HEC 10 96 10 96 Ϊ0 96 10 96
CoπΩVϊdππp. dO
[115] [116] Examples 41-46 [117] Based on the different compositions described in Table 9, 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.
[118] 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).
[119] [120] Table 9
Pharmaceutical compositions of Examples 41-46 (Unit: mg)
[121] [122] Examples 47-52 [123] Based on the different compositions described in Table 10, 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.
[124] 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).
[125] [126] Table 10
Pharmaceutical compositions of Examples 47-52 (Unit: mg)
[127] [128] Comparative examples 1-3 [129] Based on the different compositions described in Table 11, 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.
[130] 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).
[131] [132] Table 11
Pharmaceutical compositions of Comparative examples 1-3 (Unit' mg)
[133] [134] Experimental example 1 [135] Dissolution tests for each tablet, so formed by Examples 2-4, were performed to determine its dissolution profile. The dissolution profiles of six tablets each collected from these Examples were studied in 900 mL of water as a dissolution medium at rotation of 50 rpm, with a constant temperature bath at 37+0.50C. 5 mL samples were drawn at 1, 2, 4, 6, 8, 10, 12, 14, 18, and 24 hours and replenished with 2 mL of fresh dissolution medium to make 10 mL. The dissolution samples were filtered with a 0.45-D membrane filter prior to HPLC analysis. The dissolution rates were calculated, as in Fig. 1.
[136] [137] HPLC analysis for nicotinic acid [138] Column: Kromasil C (100 A, 5 D, 4.6 mmøx250 mm) or other columns with such
18 equivalent capacity
[139] Column temperature: 4O0C [140] Mobile phase: 0.005M sodium hexanesulfonate buffer/methanol/acetonitrile (50:33:17)
[141] Flow rate: 1 mL/min
[142] Injection volume: 1OD
[143] Detector: UV spectrometer (wavelength: 262 nm)
[144]
[145] The results demonstrated that the dissolution rate of nicotinic acid had a sustained release profile for 24 hours, achieving the sustained release of nicotinic acid and nicotinic acid compound or mixtures thereof via controlled release the present invention contemplates.
[146]
[147] Experimental example 2
[148] Dissolution tests for each film or separate layer, so formed by Examples 6, 13, 15,
17 and 19, were performed to determine its dissolution profile. The dissolution profiles of three films each collected from these Examples were studied in 900 mL of 0.5% sodium lauryl sulfate (pH 7.0) as a dissolution medium at rotation of 50 rpm per minute, with a constant temperature bath at 37+0.50C. 5 mL samples were drawn at 5, 10, 15, 30 minutes. The dissolution samples were filtered with a 0.45-D membrane filter prior to HPLC analysis. The dissolution rates were calculated, as illustrated in Fig. 2.
[149]
[150] HPLC analysis for simvastatin
[151] Column: Capcell pak C18 (3.0 mmx50 mm, 3 D)
[152] Column temperature: 450C
[153] Detector: UV 238 nm
[ 154] Flow rate: 1.0 mL/min
[155] Injection volume: 10 D
[156] Mobile phase: Disodium hydrogen phosphate buffer (pH 4.0)/acetonitrile (35:65)
[157]
[158] The results demonstrated that simvastatin had more fast dissolution rate, which was supported by a recrystallization inhibiting agent, such as povidone, copovidone, poloxamer, Eudragit and HP-β-cyclodextrin.
[159]
[160] Experimental example 3
[161] Dissolution tests for each coated tablet, so formed by Example 27 and Comparative example 1, were performed to determine its dissolution profile. In the same procedure as Experimental example 2, the dissolution profiles of six tablets each from these examples, respectively, were studied. The dissolution rates were illustrated in Fig. 3.
[162] The results demonstrated that in the pharmaceutical composition of the present invention containing a film- or layer-forming agent, a recrystallization inhibiting agent and a plasticizer, the dissolution rate of simvastatin had a fast release profile of more
80% within 15 minutes. [163] [164] Experimental example 4
[165] Dissolution tests for each coated tablet, so formed by Examples 41, 43, 44, 45 and
Comparative example 2, were performed to determine its dissolution profile. In the same procedures as Experimental examples 1 and 3, the dissolution rates of nicotinic acid and simvastatin were calculated, as illustrated in Figs. 4 and 5.
[166] As shown in Fig. 4, the dissolution rate of simvastatin observed in Comparative example 2 without a recrystallization inhibiting agent was remarkably low, which was inconsistent with a rapid release profile the present invention contemplates. By contrast, in the pharmaceutical composition of the present invention containing a film- or layer- forming agent, a recrystallization inhibiting agent and a plasticizer, the dissolution rate of simvastatin had a fast release profile of more 80% within 15 minutes.
[167] As shown in Fig. 5, when the dissolution rates of simvastatin and nicotinic acid were simultaneously measured, 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%.
[168]
[169] Experimental example 5
[170] Dissolution tests for each coated tablet, so formed by Examples 50, 51 and
Comparative example 3, were performed to determine its dissolution profile. In the same procedure as Experimental example 3, the dissolution rates of nicotinic acid and simvastatin were calculated, as illustrated in Fig. 6.
[171]
[172] HPLC analysis for atorvastatin
[173] Column: Luna C 18 (4.6 mmx250 mm, 5 D)
[174] Column temperature: Room temperature
[175] Detector: UV 248 nm
[176] Flow rate: 1.0 mL/min
[177] Injection volume: 10 D
[178] Mobile phase: Acetonitrile/ammonium acetate buffer (pH 4.0)/tetrahydrofuran
(25:70:5) [179] [180] The results demonstrated that in the pharmaceutical composition of the present invention containing a film- or layer-forming agent, a recrystallization inhibiting agent and a plasticizer, the dissolution rate of simvastatin had a fast release profile of more
80% within 15 minutes.
[181]
Claims
[1] A pharmaceutical composition in a tablet dosage form which can treat and prevent hyperlipidemia 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, including a recrystallization inhibiting agent that should necessarily contain in the 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; hence, the sustained release layer of the combination product provides extended release 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 a medium of physiological pH.
[2] The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is simvastatin.
[3] The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is atorvastatin.
[4] The pharmaceutical composition according to any of claims 1 to 3, wherein one or more recrystallization inhibiting agents is/are selected from the group comprising vinyl pyrrolidone family, such as polyvinyl pyrrolidone, crospovidone and polyvinyl pyrrolidone/vinylacetate copolymer; dextrin derivatives, such as cyclodextrin, dimethyl cyclodextrin, hydroxyethyl cy- clodextrin, hydroxypropyl cyclodextrin and trimethyl cyclodextrin; alkylene oxide family, such as poloxamer and polyethylene glycol and polyethylene oxide; acrylate family, such as polymethacrylate and its derivatives, and polysaccharide family, such as alginic acid and its alkali metal salt, polyvinyl acetate.
[5] The pharmaceutical composition according to any of claims 1 to 3, wherein one or more recrystallization inhibiting agents is/are selected from the group comprising copovidone, povidone, poloxamer, Eudragit and HP-β-cyclodextrin.
[6] The pharmaceutical composition according to any of claims 1 to 3, wherein one or more recrystallization inhibiting agents is/are selected from the group comprising vinyl pyrrolidone family, such as polyvinyl pyrrolidone, crospovidone and polyvinyl pyrrolidone/vinylacetate copolymer.
[7] The pharmaceutical composition according to any of claims 1 to 3, wherein the
recrystallization inhibiting agent is polyvinyl pyrrolidone.
[8] The pharmaceutical composition according to any of claims 1 to 3, wherein the recrystallization inhibiting agent is a polyvinyl pyrrolidone/vinylacetate copolymer.
[9] The pharmaceutical composition according to any of claims 1 to 3, wherein nicotinic acid, a nicotinic acid compound or mixtures thereof are selected from the group comprising nicotinic acid, nicotinyl alcohol tartrate, D-glucitol hexan- icotinate, aluminium nicotinate, niceritrol, d,l-alpha-tocopheryl nicotinate, 6-OH-nicotinic acid, nicotinaria acid, nicotinamide, nicotinamide-N-oxide, 6-OH-nicotinamide, NAD, N-methyl-l-pyridine-S-carboxamide, N- methyl-nicotinamide, N-ribosyl-l-pyridone-S-carboxide, N- methyl-4-pyridone-5-carboxamide, bradilian sorbinicate, hexanicite, ronitol and lower alcohol esters of nicotinic acid.
[10] The pharmaceutical composition according to any of claims 1 to 3, wherein the polymer in the sustained release layer includes one or more materials selected from the group comprising cellulose family, such as hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hy- droxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hy- droxyethylethylcellulose, hydroxypropylethylcellulose and alkyl hydroxypropyl- methylcellulose; polysaccharide family, such as corn starch, potato starch and alpha starch and its derivative hydroxyethyl starch, dextrin and its derivative dextran, maltodextrin, polydextrose and 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, tamarind gum, tragacanth gum and ghatti gum; peptide family, such as gelatin, collagen, protamine and zein; acrylic acid family, such as carbomer and polyacrylamide, and other materials (e.g., polyvinylacetal diethylaminoacetate, glucomannan, glucosamine, arabinogalactane, furcelleran, pullulan, polyurethane, chitosan, chitin, agar, pectin and carrageenan).
[11] The pharmaceutical composition according to any of claims 1 to 3, wherein one or more film- or layer-forming agents in the fast release layer is/are selected from the group comprising cellulose family, such as noncrystalline cellulose, hydrox- ypropylmethylcellulose, sodium carboxymethylcellulose, methylcellulose, ethyl- cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, alkyl hydrox- ypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydrox- ypropylmethylcellulose 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, casein, tara gum, tamarind gum, tragacanth gum and ghatti gum; peptide family, such as gelatin, collagen, protamine and zein; acrylic acid family, such as carbomer and polyacrylamide; wax family, such as carnauba wax and beeswax; saccharides, such as sucrose, liquid sucrose, lactose and polyvinylacetal diethylaminoacetate, and other materials (e.g., polyurethane, chitosan, chitin, agar, pectin, carrageenan and shellac).
[12] The pharmaceutical composition according to any of claims 1 to 3, wherein one or more plasticizers in the fast release layer is/are selected from the group comprising poly glyceryl fatty acid esters, poly oxy ethylene glyceryl fatty acid esters, sorbitan fatty acid esters, polyoxyethylene 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 polyoxypropylene 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, diethyl phthalate, glycerin, mineral oil and lanolin alcohol, petroleum and lanolin alcohol, triacetin and saccharides, such as triethyl citrate, sodium lauryl sulfate, docusate sodium, sorbitol and mannitol.
[13] The pharmaceutical composition according to any of claims 1 to 3, wherein a drug-free protective film with one or more layers is additionally embedded on an inner or outer part of the fast release layer.
[14] The pharmaceutical composition according to any of claims 1 to 3, wherein the fast release layer may additionally contain an anti-oxidant.
[15] The pharmaceutical composition according to according to claim 14, wherein one or more anti-oxidants is/are selected from the group comprising ascorbic acid, butylated hydroxyanisole, citric acid, tocopherol and its derivative and compound.
[16] The pharmaceutical composition according to any of claims 1 to 3, wherein the sustained release layer may additionally contain one or more commonly used diluents, binders, dis integrants, colorants, preservatives, foaming agents and lubricants; and, the fast release layer may additionally include one or more disintegration enhancing agents, dispersants, polishing agents, sunscreen agent and colorants.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020050123479A KR20070063350A (en) | 2005-12-14 | 2005-12-14 | Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis |
KR10-2005-0123479 | 2005-12-14 |
Publications (1)
Publication Number | Publication Date |
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WO2007069827A1 true WO2007069827A1 (en) | 2007-06-21 |
Family
ID=38163110
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/KR2006/004738 WO2007069827A1 (en) | 2005-12-14 | 2006-11-13 | Pharmaceutical composition with extended release layer and fast release layer for treatment of hyperlipidemia and arteriosclerosis |
Country Status (2)
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KR (1) | KR20070063350A (en) |
WO (1) | WO2007069827A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008087010A1 (en) * | 2007-01-19 | 2008-07-24 | Medice Arzneimittel Puetter Gmbh & Co. Kg | Use of nicotinamide for treatment and/or prevention of arteriosclerosis |
WO2009016577A2 (en) * | 2007-07-27 | 2009-02-05 | Ranbaxy Laboratories Limited | A pharmaceutical composition comprising atorvastatin and niacin |
WO2011154755A1 (en) | 2010-06-08 | 2011-12-15 | Nanoform Cardiovascular Therapeutics Ltd. | Nanostructured atorvastatin, its pharmaceutically acceptable salts and compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
RU2468789C1 (en) * | 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) | Medication for prevention and treatment of atheroslerosis |
US9216160B2 (en) | 2011-10-05 | 2015-12-22 | Jeffrey M. Golini | Choline composition |
CN111303907A (en) * | 2020-04-13 | 2020-06-19 | 曲阜师范大学 | Preparation method of dustproof sand-fixation environment-friendly liquid mulching material |
CN112739383A (en) * | 2018-09-19 | 2021-04-30 | 埃斯普投资有限公司 | Peroxide-stabilized polymer compositions, process for their preparation and their use |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101052947B1 (en) * | 2008-07-22 | 2011-07-29 | 한국콜마 주식회사 | Azelastine Liquid Formulation |
KR102380498B1 (en) * | 2021-02-24 | 2022-04-01 | 주식회사 청안오가닉스 | Composition for manufacturing sustained-release tablets capable of controlling sustained release of active ingredients in health functional food |
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EP0643965A1 (en) * | 1993-09-20 | 1995-03-22 | Kos Pharmaceuticals, Inc. | Nicotinic acid compositions for treating hyperlipidemia |
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US5260305A (en) * | 1988-12-12 | 1993-11-09 | E. R. Squibb & Sons, Inc. | Combination of pravastatin and nicotinic acid or related acid and method for lowering serum cholesterol using such combination |
EP0643965A1 (en) * | 1993-09-20 | 1995-03-22 | Kos Pharmaceuticals, Inc. | Nicotinic acid compositions for treating hyperlipidemia |
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008087010A1 (en) * | 2007-01-19 | 2008-07-24 | Medice Arzneimittel Puetter Gmbh & Co. Kg | Use of nicotinamide for treatment and/or prevention of arteriosclerosis |
DE102007003524A1 (en) * | 2007-01-19 | 2008-09-04 | MEDICE Arzneimittel Pütter GmbH & Co. KG | Medicines for the treatment and / or prevention of arteriosclerosis |
WO2009016577A2 (en) * | 2007-07-27 | 2009-02-05 | Ranbaxy Laboratories Limited | A pharmaceutical composition comprising atorvastatin and niacin |
WO2009016577A3 (en) * | 2007-07-27 | 2009-03-26 | Ranbaxy Lab Ltd | A pharmaceutical composition comprising atorvastatin and niacin |
WO2011154755A1 (en) | 2010-06-08 | 2011-12-15 | Nanoform Cardiovascular Therapeutics Ltd. | Nanostructured atorvastatin, its pharmaceutically acceptable salts and compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
RU2468789C1 (en) * | 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) | Medication for prevention and treatment of atheroslerosis |
US9216160B2 (en) | 2011-10-05 | 2015-12-22 | Jeffrey M. Golini | Choline composition |
CN112739383A (en) * | 2018-09-19 | 2021-04-30 | 埃斯普投资有限公司 | Peroxide-stabilized polymer compositions, process for their preparation and their use |
CN112739383B (en) * | 2018-09-19 | 2024-03-15 | 埃斯普投资有限公司 | Peroxide-stable polymer compositions, process for their preparation and their use |
CN111303907A (en) * | 2020-04-13 | 2020-06-19 | 曲阜师范大学 | Preparation method of dustproof sand-fixation environment-friendly liquid mulching material |
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