WO2004064840A1 - Composition pour le traitement de l'hyperlipidemie - Google Patents

Composition pour le traitement de l'hyperlipidemie Download PDF

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Publication number
WO2004064840A1
WO2004064840A1 PCT/CN2003/000855 CN0300855W WO2004064840A1 WO 2004064840 A1 WO2004064840 A1 WO 2004064840A1 CN 0300855 W CN0300855 W CN 0300855W WO 2004064840 A1 WO2004064840 A1 WO 2004064840A1
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lovastatin
niacin
active ingredient
composition
pvp
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PCT/CN2003/000855
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English (en)
Chinese (zh)
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Yong Sun
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Lunan Pharmaceutical Company Limited
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Priority to AU2003272864A priority Critical patent/AU2003272864A1/en
Publication of WO2004064840A1 publication Critical patent/WO2004064840A1/fr

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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/305—Mercury compounds
    • A61K31/31—Mercury compounds containing nitrogen
    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

Definitions

  • the present invention relates to a composition
  • a composition comprising nicotinic acid or a derivative of nicotinic acid and a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and the composition in the prevention and treatment of hyperlipidemia Applications.
  • HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
  • the main place where the body synthesizes endogenous cholesterol is in the liver (about 70% of the total).
  • the biosynthesis of cholesterol is firstly the condensation of two molecules of acetyl CoA to acetoacetyl CoA, which is condensed with one molecule of acetyl CoA to HMG CoA through the action of hydroxymethylglutaryl CoA synthase in the cytosol.
  • HMG CoA ((3-hydroxy- 3-methylglutaxy coenzyme A) reductase in the cytosol can catalyze the reduction of HMG CoA with a ring-opening hydroxy acid structure to mevalonate, which further produces squalene to synthesize cholesterol.
  • HMG CoA reductase It is a rate-limiting enzyme in the early stages of endogenous cholesterol biosynthesis. Inhibition of this enzyme activity will cause mevalonate to form an obstacle, hinder the synthesis of endogenous cholesterol, and reduce total plasma cholesterol (TC) levels.
  • HMG CoA reductase inhibitors because of their structure similar to HMG CoA, or their metabolites, can competitively inhibit HMG CoA reductase activity in the early stages of cholesterol synthesis, thereby reducing endogenous cholesterol synthesis and lowering blood TC levels.
  • VLDL very low density lipoprotein
  • LDL low density lipoprotein
  • LDL-C very low density lipoprotein-cholesterol
  • LDL-C Low density lipoprotein-cholesterol
  • Nicotinic acid and its derivatives can inhibit hormone-sensitive lipase by reducing the level of cyclic adenosine monophosphate (cAMP) in adipose tissue, directly inhibiting fat catabolism, making TG difficult to break down into free fatty acids (FFA), and causing blood
  • cAMP cyclic adenosine monophosphate
  • FFA free fatty acids
  • the decrease in FFA concentration and the lack of raw materials for liver synthesis of TG resulted in a decrease in VLDL synthesis and secondary reduction in LDL production.
  • the direct inhibition of VLDL synthesis by this drug may also be the cause of LDL reduction.
  • Niacin and its derivatives can reduce LDL and TG levels by reducing VLDL production, thereby reducing TC levels, that is, reducing atherogenic effects
  • Plasma lipoprotein levels due to sclerosis (AS) increase HDL levels with anti-AS effects.
  • the two drugs mentioned above have good curative effect as a hypolipidemic drug for the treatment of hyperlipidemia, but the mechanism of action is single, the antihypertensive effect is limited, and the treatment of the disease is often delayed due to failure to prescribe the right medicine. Summary of the invention
  • An object of the present invention is to provide a composition for treating hyperlipidemia, which has a significantly better curative effect than the effect of each active ingredient alone, and has no increase in adverse reactions.
  • Another object of the present invention is to make the above-mentioned composition into a sustained-release preparation, which is more convenient and safe to use, and can more effectively prevent and treat hyperlipidemia.
  • a composition for treating hyperlipidemia is characterized in that it contains two therapeutically effective amounts of active ingredients.
  • the composition and content of the composition are as follows:
  • Niacin or a derivative of Niacin a. Niacin or a derivative of Niacin
  • the weight ratio of the active ingredient a to the active ingredient b is 5-100: 1.
  • the derivative of nicotinic acid in active ingredient a of the above composition is inositol nicotinate, tocopheryl nicotinate, or aximus, preferably aximus; active ingredient b is a statin, including lovastatin (Lovastatin), Simvastatin, Pravastatin, Fluvastatin, Cerivastatin, Atorvastatin, preferably lovastatin.
  • lovastatin Lovastatin
  • Simvastatin Simvastatin
  • Pravastatin Pravastatin
  • Fluvastatin Cerivastatin
  • Atorvastatin preferably lovastatin.
  • the weight ratio of acyclomus to lovastatin is 25-50: 1, preferably 25: 1 or 37.5: 1.
  • the weight ratio of niacin to lovastatin is preferably 37.5: 1 or 50: 1.
  • the therapeutically effective amount of the active ingredient a is acyclomus, its daily dose is 250 mg-1000 mg ; in combination with the therapeutically effective amount of the active ingredient b lovastatin, its daily dose is 10 mg-80 mg.
  • the therapeutically effective amount of the active ingredient a is niacin, its daily dose is 100rag-1000mg; in combination with the therapeutically effective amount of the active ingredient b, lovastatin, its daily dose is 10mg-80mg.
  • a therapeutically effective amount of the active ingredient a and a therapeutically effective amount of the active ingredient b are mixed with one or more pharmaceutically acceptable excipients, it can be prepared into suitable preparations, such as tablets, pills, capsules, etc. .
  • the active ingredient a is preferably made into a sustained-release portion, and then is made into a sustained-release preparation such as a tablet, a pill, a capsule, etc. together with the active ingredient b.
  • pharmaceutically acceptable excipients for preparing tablets include diluents such as starch, lactose, mannitol, pregelatinized starch, dextrin, and microcrystalline cellulose; and disintegrants such as sodium carboxymethyl starch and hydroxypropyl starch.
  • PVP polyvinylpyrrolidone
  • lubricants such as glyceryl behenate, magnesium stearate, micronized silica gel, one or more combinations.
  • compositions and pills include diluents such as starch, lactose, pregelatinized starch, dextrin, microcrystalline cellulose; disintegrants such as sodium carboxymethyl starch, hydroxypropyl starch, mannitol ; Slow-release agents, such as ethyl cellulose, Eudragit (acrylic resin) RS 100, Eudragit RL 100, Eudragit RS 30D, Eudragit RL 30D, Eudragit NE 30D, Surelease (Ethyl cellulose water Dispersions); binders, such as polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone; plasticizers, such as polyethylene glycol-6000, polyethylene glycol-4000, diethyl phthalate, citric acid Triethyl ester; one or more combinations of anti-sticking agents, such as magnesium stearate, talc, and micronized silica gel.
  • diluents such as starch, lac
  • composition provided by the present invention can be administered 1 to 4 times a day, preferably twice a day.
  • the present invention has carried out pharmacological research on a therapeutically effective amount of active ingredient a, a therapeutically effective amount of active ingredient b, and the composition provided by the present invention.
  • the results show that when used to treat patients with hyperlipidemia, and When the therapeutically effective amount of the active ingredient a or the therapeutically effective amount of the active ingredient b is applied alone, the composition containing the active ingredients a and b provided by the present invention shows an amazing effect.
  • the results of activity experiments on the composition of different active ingredients show that the lipid-lowering effect of the composition of acyclomus / lovastatin is more significant.
  • the dosage range of the invention is large, the effect duration is long, the comprehensive effect is good, and the application is convenient.
  • Figure 2a, 2b, 2c The effects of acyclovir / lovastatin, niacin / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol lipid levels.
  • FIG 3 Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol lipase secretion rate (TGSR).
  • TGSR plasma lipoprotein triacylglycerol lipase secretion rate
  • Fig. 4a, 4b Effect of acyclomus / lovastatin, nicotinic acid / lovastatin, and lovastatin on chylomicron and triglyceride lipase secretion after intravenous trinitrotoluene injection .
  • Figure 5a, 5b Effect of Lovastatin / Aximus, Niacin / Lovastatin, and Lovastatin on lipoprotein lipase activity in epididymal tissue and femoral muscle.
  • Figure 6a, 6b Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipoprotein lipase and hepatic triacylglycerol lipase activity after heparinization.
  • Preparation process Aximolimus is passed through a 100-mesh sieve, sodium carboxymethyl starch and microcrystalline cellulose are passed through an 80-mesh sieve, and a prescribed amount of aximuscil is mixed with sodium carboxymethyl starch and microcrystalline cellulose. Add 20g of 6% PVP anhydrous ethanol solution to granulate, dry at 60 ° C, sieve the dry granules with 16 mesh, and add the prescribed amount of magnesium stearate to the dry granules. b,
  • Preparation process Lovastatin is passed through a 100-mesh sieve, hydroxypropyl cellulose and microcrystalline cellulose are passed through an 80-mesh sieve, and a prescribed amount of lovastatin, hydroxypropyl cellulose, and microcrystalline cellulose are mixed and mixed, and 6 is added. 50 g of anhydrous ethanol solution of% PVP was granulated, dried at 60 ° C., and the dried granules were sieved with a 16-mesh sieve. A prescribed amount of glyceryl behenate was added to the dried granules.
  • Preparation process Lovastatin passed 100 mesh sieve, hydroxypropyl cellulose, pregelatinized starch passed 80 With a mesh sieve, weigh the prescribed amount of lovastatin, hydroxypropyl cellulose, and pregelatinized starch, mix them evenly, add 50 g of 6% PVP anhydrous ethanol solution to granulate, dry at 60 ° C, and sieve the dry granules with a 16 mesh sieve Add the prescribed amount of glyceryl behenate to the dry granules.
  • Preparation process Aximolimus is passed through a 100-mesh sieve, hydroxypropyl methylcellulose-4M, microcrystalline cellulose is passed through an 80-mesh sieve, and the prescribed amount of acyclovir and hydroxypropylmethylcellulose-4M is weighed. 2. Mix the microcrystalline cellulose evenly and add 8 ° /. 150 g of anhydrous ethanol solution of PVP was granulated, dried at 60 ° C., and the dried granules were sieved with a 16-mesh sieve. A prescribed amount of magnesium stearate was added to the dried granules. Lovastatin 10g
  • Preparation process Lovastatin is passed through a 100-mesh sieve, carboxymethylcellulose sodium and lactose are passed through an 80-mesh sieve. A prescribed amount of lovastatin, sodium carboxymethylcellulose, and lactose are mixed, and 6% PVP of 95 is added. 50% of ethanol solution was granulated, dried at 60 ° C., and sieved into a thousand granules with 16 meshes. The dry granules were added with a prescribed amount of magnesium stearate.
  • Preparation process Axioximus sieved through a 100-mesh sieve, hydroxypropyl methylcellulose-4M, microcrystalline cellulose sieved through an 80-mesh sieve, and a prescribed amount of aximus and hydroxypropyl methylcellulose-4M were weighed. 1. Microcrystalline cellulose is mixed uniformly, and 120 g of 8% PVP anhydrous ethanol solution is added to granulate, dried at 60 ° C., and the dry granules are sieved with a 16 mesh sieve. The dry granules are added with a prescribed amount of magnesium stearate. Lovastatin 10g
  • Preparation process Lovastatin is passed through a 100-mesh sieve, carboxymethylcellulose sodium and lactose are passed through an 80-mesh sieve. The prescribed amount of lovastatin, sodium carboxymethylcellulose, and lactose are mixed uniformly, and 6% PVP of 95 is added. 50% of ethanol solution was granulated, dried at 60 ° C, and the dry granules were sieved with a 16 mesh sieve. The dry granules were added with a prescribed amount of magnesium stearate.
  • Preparation process Lovastatin is passed through a 100-mesh sieve, pregelatinized starch and mannitol are passed through an 80-mesh sieve, a prescribed amount of lovastatin, pregelatinized starch, and mannitol are mixed, and 6% PVP of 95% ethanol is added. 50g of the solution was granulated, dried at 60 ° C, and the dry granules were sieved with a 16-mesh sieve. The dry granules were added with a prescribed amount of micronized silica gel.
  • Nicotinic acid is passed through a 100-mesh sieve, lactose and hydroxypropyl methylcellulose-15M is passed through 80-mesh.
  • Preparation process Lovastatin is passed through a 100-mesh sieve, hydroxypropyl cellulose and dextrin are passed through an 80-mesh sieve. A prescribed amount of lovastatin, hydroxypropyl cellulose, and dextrin are mixed, and 5% of PVP 95 is added. 50% of ethanol solution was granulated, dried at 60 ° C, and the dry granules were sieved with a 16-mesh sieve. A prescribed amount of talc was added to the dry granules.
  • Preparation process Lovastatin is passed through a 100-mesh sieve, hydroxypropyl cellulose and starch are passed through an 80-mesh sieve. The prescribed amount of lovastatin, hydroxypropyl cellulose, and starch are mixed uniformly, and 6% PVP and 95% ethanol are added. 30g of the solution was granulated, dried at 60 ° C, and the dry granules were sieved with a 16-mesh sieve. A prescribed amount of talc was added to the dry granules.
  • Preparation process Pass axioxime through a 120-mesh sieve, weigh the prescription amount, and pour it into the lower hopper. Open granulating coating machine (Taiwan Yuancheng Machinery Factory), inlet air pressure 0.5 bar, inlet air temperature 30 ° C, spray gun pressure (CYL) 3 bar, atomization pressure (CAP1) 0.8 bar, pour into blank pellet core , Granulation. Feeding speed is 4 rpm, peristaltic pump is 12%, turntable speed is 145 rpm, and 7% PVP solution is sprayed (solvent is 90% ethanol). After the granulation is finished, it is dried at 50 ⁇ and the output is 420g. Lovastatin 8g
  • Preparation process The lovastatin is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Open the granulation coating machine, the inlet air pressure is 0.5 bar, the inlet air temperature is 30 ° C, CYL 3bar, CAP1 l. Obar, pour into the blank pellet core, and granulate. Feeding speed is 4 rpm, peristaltic pump is 6%, turntable speed is 160 rpm, and 7% PVP solution is sprayed (solvent is 90% ethanol). After granulation, drying at 45 ° C, discharging 60g.
  • Preparation process Aximus is sieved through a 120-mesh sieve, the prescription is weighed, and poured into the lower hopper. Open the granulating coating machine, the inlet air pressure is 0.5 bar, the inlet air temperature is 30 ° C, CYL 3bar, CAP1 0.8 bar, pour into the blank pellet core, and granulate. The feeding speed is 4 rpm, the peristaltic pump is 12%, the rotary speed is 145 rpm, and the 7% PVP solution is sprayed (the solvent is 90% ethanol). After the granulation is finished, it is dried at 50 ⁇ to discharge 580g. 580g of aximus containing pellets prepared in a
  • Surelease 90g talc powder lg pure water 50g Preparation process: Pour the aximus pill obtained in a into a turntable, turn on a granulation coating machine, the air pressure is l. Obar, the air temperature is 30 ° C, CYL 3bar, CAPl 1. 5 bar, 5% peristaltic pump, 180 rpm rotary table, spray pure aqueous solution of Surelease. After coating, drying at 50 ° C, the output was 660g.
  • the lovastatin pellets were prepared according to the requirement of b in Example 5, and the aximus pill prepared in this example b was filled with a hard capsule medicine filling machine according to each two capsules containing aximus and lovast statins and 10mg weight are filled, as can 375ni g.
  • Preparation process Nicotinic acid is passed through a 120 mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Pelletizing coating machine, inlet pressure 0.5 bar, inlet temperature 30 ° C, CYL 3bar, CAPl 0.8 bar, pour into blank pellet core and granulate. Feeding speed: 4rpm, peristaltic pump: 12%, turntable speed: 165rpm, spray with 7% PVP solution (solvent: 90% ethanol). After granulation, drying at 50 ⁇ , the output is 810g.
  • Preparation process The lovastatin is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Open the granulation coating machine, the inlet air pressure is 0.5 bar, the inlet air temperature is 30 ° C, CYL 3bar, CAPl 0. 8bar, pour into the blank pellet core, and granulate. Feeding speed is 4r P m, peristaltic pump is 12%, rotary speed is 120rpm, and 7% PVP solution is sprayed in (solvent is 90% ethanol). After granulation, drying at 45 ° C, discharging 65g. c. Fill the pellets prepared by a and b with a hard capsule medicine filling machine according to the weights of niacin and lovastatin in each two capsules being 500 mg and 10 mg, respectively.
  • Preparation process Nicotinic acid is passed through a 120 mesh sieve, the prescription amount is weighed and poured into the lower hopper. Open the granulating coating machine, the inlet air pressure is 0.5 bar, the inlet air temperature is 30 ° C, CYL 3bar, CAPl 0. 8bar, pour into the blank pellet core, and granulate. Feeding speed: 4rpm, peristaltic pump: 12%, turntable speed: 145rpm, spray 7% PVP solution (solvent: 90% ethanol). After the granulation is finished, it is dried at 50 ° C to discharge 1060g.
  • Preparation process The lovastatin is sieved through a 120-mesh sieve, the prescription amount is weighed, and poured into the lower hopper. Open the granulating coating machine, the inlet air pressure is 0.5 bar, the inlet air temperature is 30 ° C, CYL 3 bar, CAPl 0. 8 bar, pour into the blank pellet core, and granulate. Feeding speed 4rpm, peristaltic pump 12%, turntable speed 120rpm, spray Add 7% PVP solution (solvent is 90% ethanol). After granulation, drying at 45 ° C, the output is 72 g . d.
  • Example 12 Main pharmacodynamic study of acyclomus / lovastatin
  • Acyclovir / Lovastatin is 25mg / lmg / kg, 50mg / lmg / kg.
  • Experimental method-48 rats were taken. The rats were first fed with common feed under the experimental environment, observed for 8 days, then cut off the tail to take blood, centrifuged to take the serum, and measured the normal values of their blood lipid indexes. Blood lipid levels were randomly divided into four groups, each group consisting of 12 rats.
  • the first group was fed with high-fat feeds; the second, third, and fourth groups were fed with high-fat feeds at the same time, and the corresponding drugs were given orally every night; of which, the second group was given acyclovir / lovastatin 25 mg / lmg / kg or 50mg / lmg / k g; the third group was given niacin / lovastatin 100mg / lmg / kg ; the fourth group was given lovastatin 1mg / kg.
  • TGSR Ternary triglyceride lipase secretion rate
  • Luparinized plasma LPL and liver triglyceride lipase H-TGL
  • TG plasma triacylglycerol lipase
  • TC total cholesterol
  • PL phospholipids
  • FFA free fatty acids
  • LPL lipoprotein lipase
  • H-TGL liver triacylglycerol lipase
  • Figure 1 Effects of Acyclovir / Lovastatin, Niacin / Lovastatin, and Lovastatin on Plasma Lipid Levels.
  • the number of animals in the control group, acyclomus / lovastatin group, the nicotinic acid / lovastatin group, and the lovastatin group were 12, 9, 10, and 10, respectively.
  • Plasma triacylglycerols (TG), total cholesterol (TC), phospholipids (PL) and free fatty acids (FFA) were measured on day 8.
  • the results of each group are expressed as mean soil standard deviation.
  • * ⁇ ⁇ 0 ⁇ 05, ** ⁇ ⁇ 0. 01 represents the control group had significant difference compared to, # ⁇ ⁇ 0. 05, represents the lovastatin group there was a significant difference compared to.
  • FIG. 2 Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol levels.
  • Plasma lipoprotein triacylglycerol lipase levels were measured on the eighth day. Each lipoprotein component was measured according to the ultracentrifugation method.
  • Control group acyclomus / lovastatin, nicotinic acid / lovastatin, and lovastatin. The number of animals was 12, 9, 10, and 10, respectively.
  • * ⁇ ⁇ 0 .. 05, ⁇ ⁇ 0 ⁇ 01 represents the control group having a significant difference compared, # ⁇ ⁇ 0. 05, and represents a niacin / lovastatin or lovastatin group was significant compared to Sexual difference.
  • FIG. 3 Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol lipase secretion rate (TGSR).
  • the intravenous injection dose of trinitrotoluene was 600 mg / kg, and TGSR was measured at a specific time. There were 12 animals in each group.
  • TGSR is expressed in milligrams of triacylglycerol lipase secreted per minute. The results of each group are expressed as the mean ⁇ standard deviation.
  • FIG. 4 Effect of acyclomus / lovastatin, nicotinic acid / lovastatin, and lovastatin on triacylglycerol lipase secretion in chylomicrons and very low density lipoprotein after intravenous injection of trinitrotoluene
  • Plasma chylomicron-TG and very low density lipoprotein (VLDL) -TGo were measured in 12 animals in each group. The results are shown in the mean ⁇ standard deviation table Show. * P ⁇ 0. 05. ** P ⁇ 0. 01 indicates a significant difference compared to the control group, and # P ⁇ 0. 05 indicates a significant difference compared to the lovastatin group.
  • FIG. 5 Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on lipoprotein lipase activity in epididymal tissue and femoral muscle.
  • the epididymal tissue and femoral muscle tissue were taken from each group of rats.
  • Determination of lipoprotein lipase (LPL) activity There were 12 animals in each group.
  • LPL activity is expressed in millimoles per gram of free fatty acid formed per hour. The results of each group are expressed as the mean ⁇ standard deviation.
  • * P ⁇ 0.05, P ⁇ 0.01 indicates a significant difference compared with the control group.
  • # ⁇ ⁇ 0. 05 indicating a significant difference compared with lovastatin alone.
  • FIG. 6 Effect of acyclovir / Lovastatin, Nicotinic Acid / Lovastatin, and Lovastatin on heparinized hepatic lipoprotein lipase and triglyceride lipase activity
  • Heparinized plasma (PHP) in each group was obtained after heparin injection in rats.
  • Lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (H-TGL) activities were measured.
  • the number of animals in each group was 10.
  • LPL and technetium-TGL activity are expressed as the number of moles of free fatty acid formed per milliliter per hour.
  • the results of each group are expressed as mean soil standard deviation.
  • Regular administration of 7 days of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin alone can significantly reduce rat plasma TG by 12.5%, and reduce very low density lipoprotein TG by 42%.
  • Acoximus / lovastatin had no effect on TGSR in trinitrotoluene for 1.5 hours, and TGSR decreased by 26.3% for 1.5 to 3.0 hours.
  • Acyclovir / Lovastatin increased LPL activity in epididymal tissue and femoral muscle by 40% and 28%, respectively.
  • Acyclovir / Lovastatin also significantly increased LPL activity in plasma after heparinization, but had no effect on H-TGL activity.
  • Male Wistar rats fed 0.25% (w / w) acyclomus / lovastatin showed reduced plasma triglyceride levels after 14 days.
  • Both acyclovir and lovastatin have the same effect in reducing total cholesterol, LDL-C and triglycerides, and increasing HDL-C. The difference is that the mechanism of action is different. Inhibit hormone-sensitive lipase, directly inhibit fat catabolism, and reduce liver synthesis of VLDL and LDL. Lovastatin is a competitive inhibitor of HMG CoA reductase activity, thereby reducing endogenous cholesterol synthesis and lowering total cholesterol levels in plasma. Further reduced LDL-C, VLDL-C and TC levels.
  • Acyclovir / Lovastatin is mainly used for mixed hypercholesterolemia, heterozygous familial hypercholesterolemia, type III hyperlipoproteinemia, and diabetic, renal hyperlipidemia, etc.
  • Blood lipid disorders such as dyslipidemia, hypertriglyceridemia, and low HDL bloodemia have increased the range of blood lipid reduction in order to more effectively control atherosclerosis (AS), the most important cardiovascular disease that harms human health.
  • AS atherosclerosis
  • Wide, safe, reliable, and effective treatment drugs while providing patients with a simple, convenient, and feasible drug treatment, applied to the clinic, will produce strange results.
  • VLDL-lipids and VLDL-proteins were determined according to existing methods.
  • the mass ratios of VLDL-lipid, VLDL-protein to VLDL-TG are listed in parentheses in Table 1.
  • FC free cholesterol
  • EC esterified cholesterol
  • PL phospholipid
  • TG- Triacylglycerol lipase.
  • Each group consisted of 12 animals. The data of each group are the mean ⁇ standard deviation. * P ⁇ 0.05 ** P ⁇ 0.01, indicating a significant difference compared to the control group. # P ⁇ 0.05 ## P ⁇ 0.01, indicating that there is a significant difference between acyclovir / lovastatin group and the lovastatin group alone.
  • Example 13 Toxicology study 1 Acute toxicity study
  • Kunming mice weighing 18-22 g, were administered orally by gavage to observe the response of the animals after the administration. After the administration, the animals in the high-dose group had a short period of excitement, that is, activity decreased, disappeared, exhausted, and died.
  • SD rats were administered orally twice a day for 1 year in a row, and the results had no significant effect on rat weight, food intake, ophthalmology, histology, serum biochemistry, and urine analysis.
  • the liver weight of male rats in the middle and high dose groups increased significantly.
  • body weight, brain weight, and liver weight increased after half a year of administration, and increased after one year.
  • the thyroid weight of female rats in the middle dose group increased significantly.
  • Pregnant rats were given acyclovir / lovastatin 6 to 17 days of pregnancy, twice daily, and 5, 10 mg / kg postpartum, twice daily, and found that high-dose mother rats and fetuses gained weight Inhibition effect, but no teratogenic or embryotoxic effects were seen, and there was no effect on the growth and development and reproductive ability of F fetuses.

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Abstract

La présente invention concerne une composition pour le traitement de l'hyperlipidémie, qui comprend deux ingrédients actifs en une quantité efficace, à savoir « a » de la niacine ou ses dérivés et « b » un inhibiteur de la 3-hydroxy-3-méthyl-glutaryl-coenzyme A réductase, ainsi que « c » un excipient pharmaceutiquement acceptable, le rapport pondéral de l'ingrédient « a » à l'ingrédient « b » étant de 5-100 :1. Cette composition est plus efficace que si elle ne comprenait que l'ingrédient « a » ou l'ingrédient « b » et ses effets secondaires ne sont pas accrus. La préparation à libération contrôlée de cette composition présente les avantages d'avoir un effet de longue durée, d'être pratique à utiliser, et d'être plus efficace pour la prévention et le traitement de l'hyperlipidémie.
PCT/CN2003/000855 2003-01-20 2003-10-13 Composition pour le traitement de l'hyperlipidemie WO2004064840A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7777038B2 (en) 2004-09-28 2010-08-17 Otsuka Pharmaceutical Co., Ltd. Carbostyril compound

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN100358526C (zh) * 2004-05-08 2008-01-02 鲁南制药集团股份有限公司 治疗高血脂症的组合物
WO2005115393A1 (fr) * 2004-05-25 2005-12-08 Lunan Pharmaceutical Group Corporation Composition anti-hyperlipemie
HU227696B1 (en) 2006-04-13 2011-12-28 Egyt Gyogyszervegyeszeti Gyar Zinc salt of rosuvastatin, process for its preparation and pharmaceutical compositions containing it
CN101352425B (zh) * 2007-07-27 2010-11-10 鲁南制药集团股份有限公司 一种复方渗透泵控释制剂及其制备方法
CN101385730B (zh) * 2007-09-10 2010-07-21 鲁南制药集团股份有限公司 一种治疗高脂血症的渗透泵控释制剂组合物及其制备方法
CN101385729B (zh) * 2007-09-10 2010-07-21 鲁南制药集团股份有限公司 一种治疗高脂血症的渗透泵控释制剂组合物及其制备方法
CN101385731B (zh) * 2007-09-10 2010-12-15 鲁南制药集团股份有限公司 治疗高脂血症的渗透泵控释制剂组合物及其制备方法
CN101559058B (zh) * 2008-04-16 2011-07-20 北京本草天源药物研究院 一种治疗血脂异常的药物组合物
CN101590051B (zh) * 2008-05-29 2012-11-07 北京奥萨医药研究中心有限公司 含有烟酸、HMG-CoA还原酶抑制剂和α-糖苷酶抑制剂的药物组合物
CN101985039A (zh) * 2010-11-08 2011-03-16 北京阜康仁生物制药科技有限公司 一种用于抗血栓的药物组合物
CN105362586A (zh) * 2015-12-01 2016-03-02 青岛麦瑞特医药技术有限公司 一种治疗老年尿失禁的药物组合物
CN105616481A (zh) * 2016-03-03 2016-06-01 广东福寿仙生物科技有限公司 一种降血脂中西药制剂及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0373507A1 (fr) * 1988-12-12 1990-06-20 E.R. SQUIBB & SONS, INC. Combinaison d'un inhibiteur de HMG-CoA réductase et autres agents réduisant le cholestérol du sérum et méthode pour diminuer le cholestérol du sérum utilisant celle combinaison
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0373507A1 (fr) * 1988-12-12 1990-06-20 E.R. SQUIBB & SONS, INC. Combinaison d'un inhibiteur de HMG-CoA réductase et autres agents réduisant le cholestérol du sérum et méthode pour diminuer le cholestérol du sérum utilisant celle combinaison
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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Using single pravastatin or inositol niacine, or their combination for treating high level serum cholesterol", CHINA DONGMAIYINGHUA ZAIZHI, vol. 5, no. 3, 1997, pages 227 - 230 *
VACEK J.L.: "Comparation of using single lovastatin or niacin and their combination for treating high level serum cholesterol", XINXUEGUANXUEJINZHAN, vol. 6, 1996 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7777038B2 (en) 2004-09-28 2010-08-17 Otsuka Pharmaceutical Co., Ltd. Carbostyril compound

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