WO2004064840A1

WO2004064840A1 - Composition for treting hyperlipemia

Info

Publication number: WO2004064840A1
Application number: PCT/CN2003/000855
Authority: WO
Inventors: Yong Sun
Original assignee: Lunan Pharmaceutical Company Limited
Priority date: 2003-01-20
Filing date: 2003-10-13
Publication date: 2004-08-05
Also published as: CN1425374A; CN1205934C; AU2003272864A1

Abstract

The present invention relates to a composition for treating hyperlipemia comprising two active ingredients having effective amount, the ingredients and amount are: “a”, niacin or its derivatives; “b”, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; c, pharmaceutically acceptable carrier, wherein, the weight ratio of ingredient “a”and ingredient “b” is 5-100:1. The effect of the composition is much better that only using “a” or “b”, and the side effect is not increased. The controlled release of that has the advantages of long durative effect and convenience, may be more effective to present and treat hyperlipemia.

Description

Composition for treating hyperlipidemia TECHNICAL FIELD

The present invention relates to 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. Background technique

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. In this way, on the one hand, the synthesis and release of very low density lipoprotein (VLDL) is hindered by the reduction of cholesterol synthesis by liver cells; on the other hand, the low density lipoprotein (LDL) on the hepatocyte membrane is compensatedly increased through the self-regulation mechanism. The number and activity of receptors and the affinity of LDL and LDL allow a large amount of LDL in blood paddles to be taken up, metabolized into bile acids by the LDL receptor pathway, and excreted, further reducing the plasma very low density lipoprotein-cholesterol (VLDL-C ), Low density lipoprotein-cholesterol (LDL-C) and TC levels.

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 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. In addition, 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.

The above object of the present invention is achieved as follows:

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:

a. Niacin or a derivative of Niacin;.

b. 3-light-yl-3-methylglutaryl coenzyme A reductase inhibitor; and

c Pharmaceutically acceptable excipients;

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.

When the active ingredient a is acyclomus, and the active ingredient b is lovastatin, the weight ratio of acyclomus to lovastatin is 25-50: 1, preferably 25: 1 or 37.5: 1.

When the active ingredient a is niacin and the active ingredient b is lovastatin, the weight ratio of niacin to lovastatin is preferably 37.5: 1 or 50: 1.

When 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.

When 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. When 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. . In order to achieve a long-lasting therapeutic effect, 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. Among them, 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. , Low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose; slow-release agents, such as ethyl cellulose, hydroxypropyl methyl cellulose-4M, hydroxypropyl methyl cellulose-15M; binders, Such as polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone; lubricants, such as glyceryl behenate, magnesium stearate, micronized silica gel, one or more combinations.

Pharmaceutically acceptable excipients for the preparation of capsules 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. The excipient ingredients and the amounts thereof used in the present invention can enable those skilled in the art to obtain tablets, pills, and capsules of good quality by known methods.

The 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. BRIEF DESCRIPTION OF THE DRAWINGS

Figure la, lb, lc, Id. The effects of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipid levels.

Figure 2a, 2b, 2c The effects of acyclovir / lovastatin, niacin / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol lipid levels.

Figure 3 Effect of acyclovir / lovastatin, nicotinic acid / lovastatin, and lovastatin on plasma lipoprotein triacylglycerol lipase secretion rate (TGSR).

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. detailed description

The following examples further describe the present invention in detail, but it does not limit the protection scope of the present application.

Example 1 Aximus 50g

Sodium Carboxymethyl Starch 10g

Microcrystalline cellulose 4g

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,

Lovastatin 10g

Hydroxypropyl cellulose 20g

Microcrystalline cellulose 30 _g

6% PVP in anhydrous ethanol 50g

Glyceryl behenate 2g

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.

c. Adopting a double-layer laminating machine, the special-shaped punched tablets are obtained. There are 900 double-layer tablets.

Example 2

&,

Aximus 250g

30g lactose

Sodium Carboxymethyl Starch 30g

Microcrystalline cellulose 18g

6% PVP in absolute ethanol 100 g

Magnesium stearate 2g

Preparation process: Axioximus sieved through 100 mesh sieve, lactose, carboxymethyl starch

Pass 80 mesh sieve, weigh the prescribed amount of acyclovir, lactose, sodium carboxymethyl starch, microcrystalline cellulose and mix well. Add 100g of 6% PVP absolute ethanol solution to granulate, dry at 60 ° C., 16 mesh sieve Dry the granules and add the prescribed amount of magnesium stearate to the thousand granules.

b,

Lovastatin 10g

30g

Pregelatinized starch 20g

6% PVP in anhydrous ethanol 50g

Glyceryl behenate 2g

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.

c. Adopting a double-layer laminating machine, the special-shaped punched tablets are obtained. There are 850 double-layer tablets.

Aximus 375g

Hydroxypropyl Methyl Cellulose-4M 40g

Microcrystalline cellulose 30g

8% PVP in anhydrous ethanol solution 150g

Magnesium stearate

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

Carboxymethylcellulose sodium 30g

20g lactose

6% PVP in 95% ethanol solution 50g

Magnesium stearate 2g

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.

c. Use a double-layer laminating machine to obtain special-shaped punched tablets. There are 850 double-layer tablets. Example 4 Aximus 200g

Hydroxypropyl Methyl Cellulose-4M 30g

Microcrystalline cellulose 20g

8% PVP in anhydrous ethanol solution 120g

Magnesium Stearate 1. 5g

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

Carboxymethylcellulose sodium 30g

20g lactose

6% PVP in 95% ethanol solution 50g

Magnesium stearate 2g

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.

c. Adopting a double-layer laminating machine, the special-shaped punched tablets are obtained. There are 850 double-layer tablets. Example 5 Niacin 500g

Mannitol 10g

40g lactose

Microcrystalline cellulose 20g

120g of 6% PVP in 95% ethanol Weigh out the prescribed amount of niacin and mannitol, lactose, and microcrystalline cellulose and mix well. Add 6% PVP in 95% ethanol solution to 120g granules, dry at 60 ° C, dry with 16 mesh sieve, add Place

Lovastatin 10g

Pregelatinized starch 25g

25g

6% PVP in 95% ethanol solution 50g fine powder silica gel 2g

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.

Example 6 Nicotinic acid 750g

30g lactose

Hydroxypropyl methyl cellulose -15M 60g

8% PVP in 95% ethanol solution 150g

Glyceryl behenate 2g

Preparation process: Nicotinic acid is passed through a 100-mesh sieve, lactose and hydroxypropyl methylcellulose-15M is passed through 80-mesh. Weighing formula:: Niacin, lactose, and hydroxypropyl methylcellulose 15M are mixed uniformly, added

150 g of 95% ethanol solution of 8% PVP was granulated, dried at 60 ° C., and the dried granules were sieved by a 16-mesh sieve. The dried granules were added with a prescribed amount of glyceryl behenate.

15g

20g

50 g of 6% PVP in 95% ethanol Talcum powder 2g

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.

c. Adopting a double-layer laminating machine, the special-shaped punched tablets are obtained. There are 850 double-layer tablets. Example 7

1000g

45g lactose

Hydroxypropyl methyl cellulose -15M 68g

170g of 95% ethanol solution of 8% PVP, 2.5g of elm ^ glyceride Preparation process: Nicotinic acid is passed through a 100 mesh sieve, lactose, hydroxypropyl methyl cellulose-15M is passed through 80 mesh Weigh the prescription: niacin and Lactose and hydroxypropyl methylcellulose-15M were mixed and mixed, and 170g of 95% ethanol solution of 8 ° / oPVP was added to granulate, dried at 60 ° C, and the dry granules were sieved with a 16 mesh sieve. Acid glyceride.

10g

20g starch

30g of 95% ethanol in 6% PVP

Talcum powder ig

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.

c. Adopting a double-layer laminating machine, the special-shaped punched tablets are obtained. There are 850 double-layer tablets. Example 8 200 g of aximus, blank pill core

7 ° / ₀ PVP solution (solvent is 90% ethanol) 200g 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 50Ό and the output is 420g. Lovastatin 8g

Blank pill core 50g

7% PVP solution (solvent is 90% ethanol) 50g

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.

c. Fill the pellets prepared by a and b with a hard capsule medicine filling machine according to the weight of 250 mg and 10 mg of aximus and lovastatin in each two capsules, respectively. Example 9

a,

300 g of aximus, 250 g of blank pills, 7% PVP solution (90% ethanol) 200 g 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 50Ό 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.

c. 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. Example 10

3.

Nicotinic acid 500g Blank pill core 300g 7% PVP solution (solvent 90% ethanol) 200g 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 50Ό, the output is 810g.

b,

Lovastatin 10g

Blank pill core 50g

7% PVP solution (solvent is 90% ethanol) 50g

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. Example 11

>

Nicotinic acid 750g Blank pill core 300g 7% PVP solution (solvent 90% ethanol) 200 _g 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.

b,

1060g of niacin-containing pellets prepared in a

70g

150g

Polyethylene glycol-6000 12g

Talc powder 24g

95% ethanol 2400g Preparation process: Pour the niacin-containing pellets prepared in a into the lower hopper. 5Bar ，入风温度 30。 Open granulation coating machine, inlet temperature 30, inlet pressure 0.5 bar, inlet temperature 30. C, CYL 3bar, CAPl 1.0bar ₅ peristaltic pump 6%, 175 rpm of the rotary table, sprayed into a 95% ethanol solution of ethyl cellulose, stearic acid and polyethylene glycol-6000. After coating, drying at 50 ° C, output 1290g _o lovastatin 20 g

Blank pill core 50g

7% PVP solution (solvent is 90% ethanol) 50g

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. Fill the pellets prepared by b and c with a hard capsule medicine filling machine according to the weight of 750mg and 20mg of niacin and lovastatin in each two capsules, respectively. Example 12: Main pharmacodynamic study of acyclomus / lovastatin

I. Purpose: To elucidate the hypolipidemic effect of acyclovir / lovastatin

2. Methods: The pharmacodynamics research protocol related to acyclovir and lovastatin was used to observe the synergistic effect of their combined use.

Models and Methods Preventive Administration of Rat Lipid Metabolism Disorder Model

1. Animal selection: Wis tar healthy adult male rats, weighing 150-200g

2. Dosage: Acyclovir / Lovastatin is 25mg / lmg / kg, 50mg / lmg / kg.

3. 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.

Since the start of the formal experiment, animals in each group were switched to high-fat diets and corresponding drugs, and their weights were regularly weighed. Blood was measured at the end of the experiment on the 8th day to determine its various indicators. Among them, 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.

4, sample

◊Celiac blood specimen, liver

◊ Plasma, serum, plasma after heparinization

5, detection indicators

◊Lipoprotein

Ternary triglyceride lipase secretion rate (TGSR)

ΦTissue Lipoprotein Lipase (LPL)

Luparinized plasma LPL and liver triglyceride lipase (H-TGL)

Luxury lipoprotein fractionation

* Plasma triacylglycerol (TG) Fourth, data processing

Group t-test was used, SAS processing software was used, and the data were mean ± SD.

V. Experimental results

Blood samples were taken at the end of the experiment to determine its various indicators, including plasma triacylglycerol lipase (TG), total cholesterol (TC;), phospholipids (PL), free fatty acids (FFA), and plasma lipoprotein triacylglycerol. Lipase, lipoprotein lipase (LPL), liver triacylglycerol lipase (H-TGL), etc. The results are as follows (Figures 1, 2, 3, 4, 5, 6):

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. * Ρ <0 · 05, ** Ρ <0. 01, represents the control group had significant difference compared to, ^# Ρ <0. 05, represents the lovastatin group there was a significant difference compared to.

Figure 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. * Ρ <0 .. 05, Ρ <0 · 01, represents the control group having a significant difference compared, ^# Ρ <0. 05, and represents a niacin / lovastatin or lovastatin group was significant compared to Sexual difference.

Figure 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. * P <0. 05, ** P <0. 01, indicating a significant difference compared to the control group, and ^# P <0. 05, indicating a significant difference compared to the lovastatin group

Figure 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 Blood samples were collected 3 hours 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.

Figure 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. ^# Ρ <0. 05, indicating a significant difference compared with lovastatin alone.

Figure 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.

* P <0.05, and P <0.01 indicates a significant difference compared to the control group. ^# Ρ <0. 05, indicating a significant difference compared with lovastatin alone.

6. Conclusion

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.

Pharmacodynamic studies of acyclomus / lovastatin show that the combination can help plasma triglycerides Decreased lipid levels can reduce blood lipids together, and the effect is significantly higher than that of lovastatin alone. In this example, the effects of acyclovir / lovastatin and niacin / lovastatin and lovastatin alone By comparison (see Table 1), it can be inferred that the hypolipidemic effect of acyclovir / lovastatin will be significantly higher than that of nicotinic acid / lovastatin and acyclovir alone. 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. 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.

Table 1.Effects of acyclovir / lovastatin and lovastatin on VLDL composition. Grouping VLDL-lipid and VLDL-protein concentrations (mg / dl)

FC EC PL TG Protein Control 41 ± 7 34 ± 11 121 ± 21 881 ± 224 106 ± 13

(4.7) (3.9) (13.7) (100.0) (12.0) Ah / Lo 27 ± 2 * 487 ± 6 88 ± 18 * 586 ± 122 * ^# 70 ± 8 * ^#

(25 1)

A / Lo 25 ± 2 * 581 ± 6 * 89 ± 21 * 546 ± 112 ** 65 ± 3 * ^#

(50 1)

Lovastatin 29 ± 6 * 55 ± 12 * 88 ± 13 * 624 ± 153 * 83 ± 7 *

(4.7) (8.8) (14.1) (100.0) (13.3)

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. Abbreviations: 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.

2 Long-term toxicity test

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. In the high-dose group, 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.

3 Reproductive toxicity test

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.

4 Conclusion

In summary, the combined administration of lovastatin and acyclovir is significantly better than the separate administration. Adverse reactions did not increase, and the results of toxicological studies showed that the composition did not increase new toxic reactions, and was easy to use, safe, and had a precise clinical effect.

Claims

Rights request

A composition for treating hyperlipidemia, characterized in that it comprises two therapeutically effective amounts of active ingredients, and the composition and content of the composition are as follows:

a. Niacin or a derivative of niacin;

b. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and

c pharmaceutically acceptable excipients;

2. The composition according to claim 1, wherein the derivative of niacin is inositol nicotinate, tocopheryl nicotinate or aximus;

The composition according to claim 2, characterized in that said derivative of niacin is acyclovir.

4. The composition according to claim 1, wherein the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is a statin.

The composition according to claim 4, wherein the statin is lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin.

The composition according to any one of claims 1 to 5, characterized in that the active ingredient a is aximus, and the active ingredient b is lovastatin, aximus and lovastatin The weight ratio is 25-50: 1.

The composition according to claim 6, characterized in that the weight ratio of acyclomus to lovastatin is 25: 1 or 37.5: 1.

The composition according to any one of claims 1 to 5, wherein the active ingredient a is niacin, the active ingredient b is lovastatin, and the weight ratio of niacin to lovastatin is 37.5: 1 or 50: 1.

9. Use of a composition according to claims 1-8 in the preparation of a preparation for the treatment of hyperlipidemia.

The application according to claim 9, wherein the preparation is a sustained-release preparation.