CN104840963B - The pharmaceutical composition of the inhibitor containing lipoprotein-associated phospholipase A_2 and application - Google Patents
The pharmaceutical composition of the inhibitor containing lipoprotein-associated phospholipase A_2 and application Download PDFInfo
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- CN104840963B CN104840963B CN201510273876.8A CN201510273876A CN104840963B CN 104840963 B CN104840963 B CN 104840963B CN 201510273876 A CN201510273876 A CN 201510273876A CN 104840963 B CN104840963 B CN 104840963B
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- Prior art keywords
- darapladib
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- inhibitor
- lipoprotein
- associated phospholipase
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- FATBGEAMYMYZAF-UHFFFAOYSA-N oleicacidamide-heptaglycolether Natural products CCCCCCCCC=CCCCCCCCC(N)=O FATBGEAMYMYZAF-UHFFFAOYSA-N 0.000 description 1
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- 210000000056 organ Anatomy 0.000 description 1
- 229940006347 orlistat 120 mg Drugs 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- 231100000614 poison Toxicity 0.000 description 1
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- 230000009862 primary prevention Effects 0.000 description 1
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- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- OYSBZLVHMPNJMR-UHFFFAOYSA-N pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.OC(=O)C1=CC=CN=C1 OYSBZLVHMPNJMR-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 229940073490 sodium glutamate Drugs 0.000 description 1
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Abstract
The present invention relates to the pharmaceutical composition of the inhibitor containing lipoprotein-associated phospholipase A_2 and application, belong to pharmaceutical technology field.The pharmaceutical composition is made up of the one or more in lipoprotein-associated phospholipase A_2 inhibitor and following component：The first glutaryl coenzyme A of 3 hydroxyl 3 (HMG CoA) reductase inhibitor, influence cholesterol and Triglyceride Metabolism in Patients medicine, influence cholesterol absorption medicine, polysaccharide fat-reducing medicament, gastrointestinal lipases inhibitor or butylphenyl phthaleine.Pharmaceutical composition provided by the invention has the effect of unexpected in terms of atherosclerosis disease is treated, and this is that previous fat-reducing medicament institute is irrealizable.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and its application, more particularly to a kind of lipoprotein-associated phospholipase A_2 that contains to press down
The pharmaceutical composition of preparation and application, belong to pharmaceutical technology field.
Background technology
Atherosclerosis (atherosclerosis) is common and most important one kind in genus of stiff vessel diseases, disease
Change takes place mostly in sustainer, coronary artery and cerebral artery, and the arteria renalis and mesenteric artery also have generation.Its pathological change is tired out
And under arterial vascular inner membrance, inner membrance and middle level.Diseased region has lipid accumulation, and invades iuntercellular under intracellular or inner membrance
Gap, cause smooth muscle cell and connective tissue proliferation, bleeding, thrombosis and calcinosis.Due to the inside and outside lipid product of cell
It is poly- obvious, it is athero- in yellow in the lipid outward appearance of endarterium, therefore turn into atherosclerosis.The dynamic of atherosis occurs
Vascular wall thickening is hardened, and elasticity weakens, and tube chamber reduces, and ischemic lesions can occur for institute's dominating organs.
The pathogenesis of atherosclerosis not yet illustrates completely, but has proven to the lipid in atheromatous plaque and be mainly derived from
Blood plasma.Thus, it is considered that this sick generation and disorders of lipid metabolism and hyperlipemia relation are very close.Blood fat includes courage
The non-water soluble substances such as sterol, triglycerides and phosphatide, these materials are combined into compound-lipoprotein with apolipoprotein.Fat egg
Blood plasma is dissolved in vain, and whole body is transported to blood circulation.
According to the difference of density, the lipoprotein in human plasma can be divided into four kinds of main Types, i.e., chylomicron (CM),
VLDL (VLDL), low-density lipoprotein (LDL), HDL (HDL).Human body hyperlipemia, mainly
It is that VLDL and LDL increase in blood plasma, immerses arterial wall, cause atherosclerosis.
It preventing and treating to atherosclerosis, should keep on a diet first, limit energy intake, advocate low cholesterol etc.；Avoid
Promote the hazards of atherosclerosis occurrence and development, such as smoking；Active treatment relevant disease, such as hypertension, diabetes
Deng.On the medicine of antiatherosclerosis, clinically use still based on lipid regulating agent.
Common drug is as follows：
1.3- hydroxyls -3 first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, including Lovastatin (Lovastatin),
Pravastatin (Pravastatin), Simvastatin (Simvastatin), Atorvastatin (Atorvastatin), fluorine cuts down him
Spit of fland (Fluvastatin), meglutol (Meglutol) etc..
2. cholesterol and Triglyceride Metabolism in Patients medicine are influenceed, including：Clofibrate (Clofibrate), fenofibrate
(Fenofibrate), Bezafibrate (Bezafibrate), Gemfibrozil (Gemfibrozil), ciprofibrate
(Ciprofibrate), Etophylline Clofibrate (also known as Etofylline Clofibrate, Theofibrate), Lifibrate (Lifibrate), benzyl chloride
Bei Te (Beclobrate), ronifibrate (Ronifibrate), Clinofibrate (Clinofibrate), Acipimox
(Acipimox), nicotinic acid (Nicotinic acid), hexanicit (Inositol nicotinate), vitamin E nicotinic acid
Ester (Vitamin E Nicotinicate), probucol (Probucol), linoleic acid (linoleic acid), pancreatopeptidase E
(Elastase), Furazabol (Furazabol), hyodeeoxycholic acid (Hyodeoxycholic acid), dextrothyroxine
(Dextrothyroxine), profit flutter this too, Riboflavin Tetrabutyrate (Riboflavin tetrabutyrate), pantethine
(pantethin, Pantethine) etc..
3. cholesterol absorption medicine is influenceed, including Ezetimibe (ezetimibe, ezetimibe), Cholestyramine, Jiang Dan Portugals
Amine DEAE (Saphadex), divistyramine (Divistyramine), methyl linoleamide (Melinamide) etc..
4. polyose medicament, including：PSS (polysaccharide sulfate), chondroitin sulfate A (CSA)
(Chondroitine Sulfate A), dextren sulfate (Dextran Sulfate Sodium) etc..
Massive epidemiology and clinical research confirmation, dyslipidemia are one of most important risk factors of cardiovascular diseases.
In more than ten years of past, a series of landmark lipid-loweringing experiments are successively completed both at home and abroad, and these results of study effectively demonstrate
Using the significance in statin cholesterol lowering therapeutic related cardiovascular disease primary and secondary prevention.
Active intervention dyslipidemia is the important measures for preventing and treating atherosclerotic cardiovascular disease, and is effectively reduced
LDL-C and total cholesterol level are then its core strategies.Although there is a variety of lipid-regulation medicines to be available for Clinical Selection at present, these
Influence of the medicine to plasma lipid profile is different.
In clinical practice, still can not be up to standard using many hypercholesterolemiapatients patients after predose statin treatment, this
When can have two kinds of selections：Increase statin dosage or use in conjunction other lipid-regulation medicines.A large amount of clinical researches show, statin agent
The effect of its norcholesterol only increases by 6% or so, but the adverse reaction related to statin treatment (particularly hepatotoxicity wind agitation after amount doubles
With muscle poison) but dramatically increase, cause some patientss not to be resistant to the statin treatment of larger dose.Therefore, some patients need
Drug combination can be by LDL-C and T-CHOL control below desired value.In general, use in conjunction statin and other tune
Fat medicine had both contributed to further to reduce T-CHOL and LDL-C is horizontal, can also effectively treat low HDL-C mass formed by blood stasis and high glycerine
The mixed dyslipidemias such as three ester mass formed by blood stasis.
For example, statins and the athero- artery sclerosis of Ezetimibe compound drug treatment, Application No. PCT/EP2009/
066033 compound preparation preparation technology of the patent application protection containing Simvastatin and Ezetimibe.Application No. PCT/
EP2006/006369 patent application protection Simvastatin and Ezetimibe compound coating tablet, coatings can effective isolating oxygen
Moisture in gas and air, to prevent drug degradation.Application No. PCT/JP2004/019159 patent application protection HMG-
The composition of CoA reductase inhibitors and Ezetimibe.
Ezetimibe is used in combination with statins, can be directed to internal two kinds of cholesterol main source-generation and suction
Link is received, while plays strong inhibitory action, this use in conjunction provides new approach for cholesterol lowering therapeutic, hence it is evident that
Improve drop LDL-C compliance rate.
New therapy target and new medicine are being sought always for reducing blood fat and treatment atherosclerosis, scientist
Composition is in the hope of reaching more preferable therapeutic effect.
Darapladib is a kind of oral lipoprotein phospholipase A2 (Lp-PLA2) inhibitor that Ge Lansu is newly researched and developed.
Darapladib is a kind of proinflammatory tune lipase that researcher cloned and depicted its feature first in 1994, it
It is one of main anti-inflammatory atherosclerosis drug target.The Phospholipids being oxidized in Lp-PLA2 hydrolyzables LDL, produce life
Active substances, activate inflammation and pro-atherogenic path on vascular wall.Lp-PLA2 inhibitor is likely to become statin
The expected sales forecast for supporting this kind of medicine huge of clinic of class ancillary drug.
Its structure is as follows：
In II clinical trial phase, darapladib can significantly inhibit the increasing of atherosclerotic plaque necrotic cores volume
Long, the mechanism of action is to directly act on atherosclerotic plaque, and can stablize patch, prevent plaque rupture, but the medicine
The phase of thing three clinic is alone to delay the ineffective of myocardial infarction.
The content of the invention
It is an object of the present invention to provide pharmaceutical composition, said composition can reach required treatment Atherosclerosis
The target level of change.
The first object of the present invention is to provide a kind of pharmaceutical composition of inhibitor containing lipoprotein-associated phospholipase A_2, its
It is made up of the one or more in lipoprotein-associated phospholipase A_2 inhibitor and following component：The first glutaryl coenzyme A of 3- hydroxyls -3
(HMG-CoA) reductase inhibitor, influence cholesterol and Triglyceride Metabolism in Patients medicine, influence cholesterol absorption medicine, polysaccharide
Fat-reducing medicament, gastrointestinal lipases inhibitor or butylphenyl phthaleine.
Specifically, in described pharmaceutical composition lipoprotein-associated phospholipase A_2 inhibitor and one kind in following component or
It is several according to weight ratio for composition：3- hydroxyls -3 first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, influence cholesterol and sweet
Oily three ester metabolic drugs, influence cholesterol absorption medicine, polysaccharide fat-reducing medicament, gastrointestinal lipases inhibitor or butylphenyl phthaleine；
Preferably, in described pharmaceutical composition lipoprotein-associated phospholipase A_2 inhibitor and one kind in following component or
It is several according to weight ratio for composition：3- hydroxyls -3 first glutaryl coenzyme A (HMG-CoA) reductase inhibitor, influence cholesterol and sweet
Oily three ester metabolic drugs, influence cholesterol absorption medicine, polysaccharide fat-reducing medicament, gastrointestinal lipases inhibitor or butylphenyl phthaleine；
Lipoprotein-associated phospholipase A_2 inhibitor and 3- hydroxyls -3 first glutaryl coenzyme A (HMG-CoA) reductase inhibitor
Weight ratio be (1 ︰ 6-1 ︰ 10), be preferably (1 ︰ 7-1 ︰ 9)；Lipoprotein-associated phospholipase A_2 inhibitor and influence cholesterol
With the weight ratio (1 ︰ 1-1 ︰ 10) of Triglyceride Metabolism in Patients medicine, it is preferably (1 ︰ 1-1 ︰ 7)；
Lipoprotein-associated phospholipase A_2 inhibitor and the weight ratio (1 ︰ 5-1 ︰ 20) for influenceing cholesterol absorption medicine, preferably
For (1 ︰ 8-1 ︰ 18)；
The weight of lipoprotein-associated phospholipase A_2 inhibitor and polysaccharide fat-reducing medicament ratio (1 ︰ 1-1 ︰ 3), it is preferably (1 ︰
1.5-1 ︰ 2)；
Lipoprotein-associated phospholipase A_2 inhibitor and the weight of gastrointestinal lipases inhibitor or butylphenyl phthaleine ratio (1 ︰ 0.5-
1 ︰ 10), be preferably (1 ︰ 1-1 ︰ 9).
In aforementioned pharmaceutical compositions：
The weight can be unit of weight known to the field of medicaments such as μ g, mg, g, kg or its multiple, such as 1/
10th, 1/100,10 times, 100 times etc..
Described first glutaryl coenzyme A (HMG-CoA) reductase inhibitor of 3- hydroxyls -3 is Lovastatin, Pravastatin, pungent cut down
Statin, Atorvastatin, Fluvastatin, meglutol and its corresponding salt, preferably Atorvastatin and its corresponding salt；
The influence cholesterol and Triglyceride Metabolism in Patients medicine are Clofibrate, fenofibrate, Bezafibrate, Ji Feibei
Together, ciprofibrate, Etophylline Clofibrate, Lifibrate, Beclobrate, ronifibrate, Clinofibrate, Acipimox, nicotinic acid,
Hexanicit, vitamine E nicotinate, probucol, linoleic acid, pancreatopeptidase E, Furazabol, hyodeeoxycholic acid, dextrorotation first shape
Parathyrine, profit flutter this too, Riboflavin Tetrabutyrate or pantethine；
The influence cholesterol absorption medicine is that Ezetimibe, Cholestyramine, DEAE-sephadex DEAE, divistyramine or first are sub-
Oleamide, preferably Ezetimibe；
The polysaccharide fat-reducing medicament is PSS, chondroitin sulfate A (CSA) or dextren sulfate；
The gastrointestinal lipases inhibitor is orlistat；
The butylphenyl phthaleine is one kind in dl-3-n-butylphthalide, levo butyl phthalide or d-3-n-butylphthalide.
Present invention also offers the preparation containing aforementioned pharmaceutical compositions, by aforementioned pharmaceutical compositions and pharmaceutically acceptable
Carrier.
The preparation is tablet, capsule, granule etc..
State pharmaceutically acceptable carrier and refer to the conventional pharmaceutical carrier of pharmaceutical field, selected from filler, adhesive, disintegration
One or more in agent, lubricant, solubilizer.
The filler is selected from starch, pregelatinized starch, beta-schardinger dextrin, lactose, preferably microcrystalline cellulose, microcrystalline cellulose
Element, lactose or beta-schardinger dextrin；
The disintegrant is selected from Ac-Di-Sol, preferably PVPP, PVPP；
The lubricant is selected from magnesium stearate, preferably talcum powder, magnesium stearate；
Described adhesive is selected from HPMC, preferably PVP, PVP；
The solubilizer is selected from polysorbate (tween), lauryl sodium sulfate；Preferably sodium dodecyl sulfate.
Present invention also offers aforementioned pharmaceutical compositions or preparation answering in the medicine of atherosclerosis disease is prepared
With.
Pharmaceutical composition provided by the invention has the characteristics that：
Lipoprotein-associated phospholipase A_2 inhibitor is alone to delay the ineffective of myocardial infarction in clinical test, but
It is that inventor is found surprisingly that, lipoprotein-associated phospholipase A_2 inhibitor and the first glutaryl coenzyme A (HMG-CoA) of 3- hydroxyls -3
Reductase inhibitor, influence cholesterol and Triglyceride Metabolism in Patients medicine, influence cholesterol absorption medicine, polysaccharide fat-reducing medicament,
One or more of use in conjunction in gastrointestinal lipases inhibitor have people's will in terms of atherosclerosis disease is treated
The effect of material, this is that previous fat-reducing medicament institute is irrealizable.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Experimental example 1：Lovastatin+Darapladib pharmacological action
1st, animal is only randomly divided into 7 with being grouped healthy NIH8 week old male mice 105, every group 15, wherein：
1 group is Normal group, gavages distilled water；
2 groups are hyperlipidemia model group, and gavage gives high cholesterol emulsion；
3 groups are Lovastatin group, gavage Lovastatin 4mg/kg；
4 groups are Darapladib groups, gavage Darapladib 30mg/kg；
5 groups are Lovastatin+Darapladib middle dose groups：Gavage Lovastatin 4mg/kg and Darapladib 30mg/
kg。
6 groups are Lovastatin+Darapladib small dose groups：Gavage Lovastatin 2mg/kg and Darapladib 20mg/
kg。
7 groups are Lovastatin+Darapladib heavy dose groups：Gavage Lovastatin 6mg/kg and Darapladib 40mg/
kg。
3 groups to 7 groups gavage high cholesterol emulsion, and every morning gives test medicine, gives high cholesterol emulsion afternoon, even
Parameters are determined after continuous 14 days.
2nd, test procedure accurate measurement Mice Body under ether light anaesthesia is grown（From nose to the length of anus）, and by following
Formula calculates obesity index=body weight1/2× body is grown（cm）×1000.After animal is put to death, both sides groin is carefully taken, around kidney
And abdominal cavity is all fatty, weighs weight in wet base respectively.
3rd, result of the test：See Tables 1 and 2
Influence (n=15, mean value ± sides of the Lovastatin+Darapladib of table 1 to high fat mouse weight and body fat
Difference)
Note：Compared with model group, * P<0.05,**P<0.01.
Influences (n=15, mean value ± variance) of the Lovastatin+Darapladib of table 2 to high fat mouse lipid
Note：Compared with model group, * P<0.05,**P<0.01.
Table 1,2 results show, Lovastatin, Darapladib and the large, medium and small each dosage of Lovastatin+Darapladib
Group plays the role of reducing blood lipid, but compared with Lovastatin, Darapladib is used alone, Lovastatin+Darapladib's
Pharmacological action is stronger, and composition small dose group can also play more excellent lipid-lowering effect.
Embodiment 2：Darapladib and Lovastatin tablet
1st, prescription (1000)
| Composition | Weight (g) | Percentage (%) |
| Darapladib | 80 | 31.68 |
| Lovastatin | 10 | 3.96 |
| Microcrystalline cellulose | 100 | 39.60 |
| PVPP | 4 | 1.58 |
| Lactose | 50 | 19.80 |
| PVP | 6 | 2.38 |
| Purified water | 50 | — |
| Magnesium stearate | 2.5 | 0.99 |
| It is total | 252.5 | 100.00 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to prescription, takes Darapladib, Lovastatin, microcrystalline cellulose, PVPP and breast
Sugar is well mixed, standby.
2) take recipe quantity PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
3) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, tabletting.
Fenofibrate+the Darapladib of experimental example 3 pharmacological action
1st, animal and packet NIH mouse totally 70, male and female half and half, are divided into 7 groups, every group 10, wherein：
1 group is Normal group, NIH5 monthly ages non-moulding normal mouse；
2 groups, 3 groups, 4 groups, 5 groups, 6 groups, 7 groups are 5 monthly age obesity mices, and 2 groups are model control group；3 groups are fenofibrate
Group, the mg/kg of gavage fenofibrate 50；4 groups are Darapladib groups, the mg/kg of gavage Darapladib 26；5 groups are fenofibrate
Spy's+Darapladib middle dose groups, gavage fenofibrate+Darapladib 76 mg/kg, wherein fenofibrate 50mg/kg；6
It is fenofibrate+Darapladib small dose groups to organize, gavage fenofibrate+Darapladib 60mg/kg, wherein fenofibrate
40mg/kg；7 groups are fenofibrate+Darapladib heavy dose groups, gavage fenofibrate+Darapladib 90mg/kg, wherein
Fenofibrate 60mg/kg, continuous gavage determine parameters after 1 month.
2nd, on the same day for preparing suckling mouse birth of Mice model of obesity, sodium glutamate 2mg/g is subcutaneously injected daily, continuously
5 days, every dams fed suckling mouse 4-6 only, and give nutrient fodder (basal feed adds 10% milk powder).From after the ablactation of 4 week old,
Fed to young mouse with nutrient fodder, progressive is got fat after 6 week old.When being tended towards stability to 5 monthly age obese degrees, for above-mentioned experiment
With.
3rd, test procedure accurate measurement Mice Body under ether light anaesthesia is grown（From nose to the length of anus）, and by following
Formula calculates obesity index=body weight1/2Body is grown（cm）*1000.After animal is put to death, both sides groin is carefully taken, around kidney and abdomen
Chamber is all fatty, weighs weight in wet base respectively.
4th, result of the test：It is shown in Table 3 and table 4
Fenofibrate+the Darapladib of table 3 is to obesity mice body weight and influence (n=10, the mean value ± side of body fat
Difference)
Note：Compared with model group, * P<0.05,**P<0.01.
Influences (mean value ± variance) of the fenofibrate+Darapladib of table 4 to obesity mice lipid
Note：Compared with model group, * P<0.05,**P<0.01.
Shown according to table 3,4 results, the large, medium and small each dosage of fenofibrate, Darapladib, fenofibrate+Darapladib
Play the role of to reduce obesity mice fat between group, but compared with fenofibrate, Darapladib is used alone, fenofibrate+
Darapladib combination effect is stronger, and composition small dose group can also play more excellent lipid-lowering effect.
The tablet of the fenofibrate of embodiment 4 and Darapladib
1st, prescription (1000)
| Composition | Weight (g) | Percentage by weight (%) |
| Darapladib | 80 | 20 |
| Fenofibrate | 100 | 25 |
| Microcrystalline cellulose | 100 | 25 |
| PVPP | 5 | 1.25 |
| Lactose | 100 | 25 |
| PVP | 10 | 2.5 |
| Purified water | 100 | — |
| Magnesium stearate | 5 | 1.25 |
| It is total | 400 | 100 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to prescription, takes Darapladib, fenofibrate, microcrystalline cellulose, PVPP, lactose
It is well mixed, it is standby.
2) take recipe quantity PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
3) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, tabletting.
Probucol+the Darapladib of experimental example 5 pharmacological action and the preparation of capsule
1st, experimental animal and packet healthy adult SD rat 70, male and female half and half, body weight 200-220g, every group 10, its
In：
1 group is Normal group；
2 groups are hyperlipidemia model group, and after high blood lipid model is successful, conventional feed is fed；
3 groups are probucol group, gavage probucol 80mg/kg；
4 groups are Darapladib groups, gavage Darapladib 20mg/kg；
5 groups are probucol+Darapladib middle dose groups, gavage probucol+Darapladib 100mg/kg, its
Middle probucol 80mg/kg.
6 groups are probucol+Darapladib small dose groups, gavage probucol+Darapladib 70mg/kg, wherein
Probucol 60mg/kg.
7 groups are probucol+Darapladib heavy dose groups, gavage probucol+Darapladib 130mg/kg, its
Middle probucol 100mg/kg.
Wherein 3-7 groups give high lipid food, and free choice feeding is continuous to feed 14 days.
2nd, the basal feed of preparation 80% of high lipid food, 5% cholesterol, 10% butter, 4% yolk powder, 0.5% methyl sulphur
Oxygen pyrimidine, 0.5% cholate mixing post-processing make pellet, 75 degrees Celsius of drying.
3rd, statistical method：
4th, result of the test：It is shown in Table 5 and table 6
Influences (n=10, mean value ± variance) of the probucol+Darapladib of table 5 to the TC contents of rat blood
Note：Compared with model group, * P<0.05,**P<0.01.
Influences (n=10, mean value ± variance) of the probucol+Darapladib of table 6 to the TG contents of rat blood
Note：Compared with model group, * P<0.05,**P<0.01.
Table 5,6 results show that probucol, Darapladib and the big-and-middle small dose groups of probucol+Darapladib are equal
Having reduces the blood fat of High fat diet rats, but compared with probucol, Darapladib is used alone, probucol+
Darapladib combination effect is stronger.Composition small dose group can also play more excellent lipid-lowering effect.
Probucol+the Darapladib of embodiment 6 capsule
1st, prescription (1000)
| Composition | Weight (g) | Percentage by weight (%) |
| Darapladib | 40 | 10 |
| Probucol | 250 | 62.5 |
| Microcrystalline cellulose | 50 | 12.5 |
| Lactose | 46 | 11.5 |
| PVP | 10 | 2.5 |
| Purified water | 80 | — |
| Magnesium stearate | 4 | 1 |
| It is total | 400 | 100 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to prescription, takes Darapladib, probucol, microcrystalline cellulose, lactose to be well mixed, it is standby
With.
2) take recipe quantity PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
3) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, by Darapladib 40mg/ grains, the filling capsule of probucol 250mg/ grains.
Experimental example 7：Ezetimibe+Darapladib pharmacological action
1st, experimental animal and packet healthy adult SD rat 70, male and female half and half, body weight 200-220g, wherein：
1 group is Normal group；
2 groups are hyperlipidemia model group, and after high blood lipid model is successful, conventional feed is fed；
3 groups are Ezetimibe group, gavage Ezetimibe 3mg/kg；
4 groups are Darapladib groups, Darapladib 27mg/kg；
5 groups are Ezetimibe+Darapladib middle dose groups, gavage Ezetimibe+Darapladib 30mg/kg groups, its
Middle Ezetimibe 3mg/kg.
6 groups are Ezetimibe+Darapladib small dose groups, gavage Ezetimibe+Darapladib 20mg/kg groups, its
Middle Ezetimibe 2mg/kg.
7 groups are Ezetimibe+Darapladib heavy dose groups, gavage Ezetimibe+Darapladib 40mg/kg groups, its
Middle Ezetimibe 4mg/kg.
Above-mentioned 3-7 groups give high lipid food, and free choice feeding is continuous to feed 14 days, 60 is daily fed afterwards with normal diet.
Determine plasma C AMP contents.
2nd, the preparation of high lipid food is the same as embodiment 3.
3rd, statistical method：
4th, result of the test：It is shown in Table 7
Influences (n=10, mean value ± variance) of the Ezetimibe+Darapladib of table 7 to the CAMP contents of rat blood
Note：Compared with model group, * P<0.05,**P<0.01.
The result of table 7 shows that Ezetimibe, Darapladib, the big-and-middle small dose groups of Ezetimibe+Darapladib have drop
The blood fat of low High fat diet rats, but compared with Ezetimibe, Darapladib is used alone, Ezetimibe+Darapladib
Combination effect it is stronger.Composition small dose group can also play more excellent lipid-lowering effect.
Ezetimibe+the Darapladib of embodiment 8 capsule
1st, prescription (1000)
| Composition | Dosage (g) | Percentage by weight (%) |
| Darapladib | 80 | 33.33 |
| Ezetimibe | 5 | 2.08 |
| Microcrystalline cellulose 302 | 150 | 62.50 |
| Magnesium stearate | 5 | 2.08 |
| It is total | 240 | 100.00 |
2nd, preparation technology
1) each composition is weighed according to prescription, then takes Darapladib, Ezetimibe, microcrystalline cellulose 302 well mixed,
It is standby.
2) supplementary material mixed addition magnesium stearate is well mixed, by Darapladib 80mg/ grains, Ezetimibe
The filling capsule of 5mg/ grains.
PSS+the Darapladib of experimental example 9 pharmacological action
1st, experimental animal and packet healthy adult SD rat 70, male and female half and half, body weight 200-220g, wherein：
1 group is Normal group；
2 groups are hyperlipidemia model control group, and after high blood lipid model is successful, conventional feed is fed；
3 groups are PSS group, gavage PSS 25mg/kg；
4 groups are Darapladib groups, fill Darapladib 15mg/kg
5 groups are PSS+Darapladib middle dose groups, gavage PSS+Darapladib 40mg/kg,
Wherein, PSS 25mg/kg.
6 groups are PSS+Darapladib small dose groups, gavage PSS+Darapladib 30mg/kg,
Wherein, PSS 20mg/kg.
7 groups are PSS+Darapladib groups, gavage PSS+Darapladib 50mg/kg, wherein,
PSS 30mg/kg.
Wherein 3-7 groups give high lipid food, and free choice feeding is continuous to feed 14 days, determine TC, TG and high density in blood plasma
The cholesterol of lipoprotein 2 (HDL2C).
2nd, statistical method：
3rd, result of the test：It is shown in Table 8.
PSS+the Darapladib of table 8 pharmacological action (n=10, mean value ± variance)
Note：Compared with model group, * P<0.05,**P<0.01.
The result of table 8 shows that PSS, Darapladib, the big-and-middle small dose groups of PSS+Darapladib are equal
Having reduces the blood fat of High fat diet rats, but compared with PSS, Darapladib is used alone, PSS+
Darapladib combination effect is stronger.Composition small dose group can also play more excellent lipid-lowering effect.
PSS+Darapladib the capsules of embodiment 10
1st, prescription (1000)
| Composition | Weight (g) | Percentage by weight (%) |
| Darapladib | 80 | 26.67 |
| PSS | 50 | 16.67 |
| Microcrystalline cellulose | 75 | 25.00 |
| Lactose | 82 | 27.33 |
| PVPP | 5 | 1.67 |
| PVP | 5 | 1.67 |
| Purified water | 50 | — |
| Magnesium stearate | 3 | 1.00 |
| It is total | 300 | 100.00 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to recipe quantity, takes Darapladib, PSS, microcrystalline cellulose, lactose, crosslinking poly-
Dimension ketone is well mixed, standby.
2) take PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
3) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, by Darapladib 80mg/ grains, the filling capsule of PSS 50mg/ grains.
Orlistat+the Darapladib of experimental example 11 pharmacological action
1st, experimental animal and packet healthy adult SD rat 70, male and female half and half, body weight 200-220g, every group 10, its
In：
1 group is Normal group；
2 groups are hyperlipidemia model control group, and after high blood lipid model is successful, conventional feed is fed；
3 groups are orlistat group, gavage orlistat 30mg/kg；
4 groups are Darapladib groups, Darapladib 20mg/kg
5 groups are orlistat+Darapladib middle dose groups, gavage orlistat+Darapladib 50mg/kg, wherein
Orlistat 30mg/kg.
6 groups are orlistat+Darapladib small dose groups, gavage orlistat+Darapladib 30mg/kg, wherein
Orlistat 20mg/kg.
7 groups are orlistat+Darapladib heavy dose groups, gavage orlistat+Darapladib 70mg/kg, wherein
Orlistat 40mg/kg.
Wherein 3-7 groups give high lipid food, and free choice feeding is continuous to feed 14 days, TC, TG, high density in measure blood plasma
Lipoprotein (HDLC) and low-density lipoprotein (DLC).
2nd, result of the test：It is shown in Table 9.
Orlistat+the Darapladib of table 9 pharmacological action (n=10, mean value ± variance)
Note：Compared with model group, * P<0.05,**P<0.01.
According to table 9, orlistat, Darapladib, the big-and-middle small dose groups of orlistat+Darapladib have drop
The blood fat of low High fat diet rats, but compared with orlistat, Darapladib is used alone, orlistat+Darapladib
Combination effect it is stronger.Composition small dose group can also play more excellent lipid-lowering effect.
Orlistat+Darapladib the capsules of embodiment 12
1st, prescription (1000)
| Composition | Dosage (g) | Percentage (%) |
| Darapladib | 80 | 20.51 |
| Orlistat | 120 | 30.77 |
| Microcrystalline cellulose | 75 | 19.23 |
| Lactose | 100 | 25.64 |
| Lauryl sodium sulfate | 2 | 0.51 |
| PVP | 8 | 2.05 |
| Purified water | 80 | — |
| Magnesium stearate | 5 | 1.28 |
| It is total | 390 | 100 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to prescription, takes Darapladib, probucol, microcrystalline cellulose, lactose, dodecyl sulphur
Sour sodium is well mixed, standby.
2) take recipe quantity PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
3) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, by Darapladib 80mg/ grains, the filling capsule of orlistat 120mg/ grains.
Butylphenyl phthaleine+the Darapladib of embodiment 13 pharmacological action
1st, experimental animal and packet take male mice 70, body weight 18-22g, are randomly divided into 7 groups, every group 10, wherein：
1 group is Normal group；
2 groups are model control group；
3 groups are butylphenyl phthaleine, gavage butylphenyl phthaleine 130mg/kg；
4 groups are Darapladib groups, gavage Darapladib 20mg/kg,
5 groups are butylphenyl phthaleine+Darapladib middle dose groups, gavage butylphenyl phthaleine+Darapladib 150mg/kg, wherein fourth
Phthalide 130mg/kg.
6 groups are butylphenyl phthaleine+Darapladib small dose groups, gavage butylphenyl phthaleine+Darapladib 100mg/kg, wherein fourth
Phthalide 90mg/kg.
7 groups are butylphenyl phthaleine+Darapladib heavy dose groups, gavage butylphenyl phthaleine+Darapladib 200mg/kg, wherein fourth
Phthalide 170mg/kg.
Normal control and model control group gavage distilled water, continuous 5 points, 2 hours after last 1 gavage, difference abdominal cavity
Inject 75% egg-nog 0.3ml/ only, except blank group, after 20 hours, gather eye socket blood, determine TC, TG, HDLC and DLC.
2nd, result of the test：It is shown in Table 10.
Butylphenyl phthaleine+the Darapladib of table 10 pharmacological action (n=10, mean value ± variance)
Note：Compared with model group, * P<0.05,**P<0.01.
The result of table 10 shows：Butylphenyl phthaleine, Darapladib, butylphenyl phthaleine+Darapladib have the blood for reducing High fat diet rats
Fat acts on, but compared with butylphenyl phthaleine is used alone, Darapladib, butylphenyl phthaleine+Darapladib combination effect is stronger.Group
Compound small dose group can also play more excellent lipid-lowering effect.
Butylphenyl phthaleine+Darapladib the granules of embodiment 14
1st, prescription (1000 bags)
| Composition | Dosage (g) | Percentage (%) |
| Darapladib | 80 | 2.67 |
| Levo butyl phthalide | 100 | 3.33 |
| Beta-schardinger dextrin | 500 | 16.67 |
| Microcrystalline cellulose | 210 | 7.00 |
| Lactose | 1000 | 33.33 |
| Mannitol | 1020 | 34.00 |
| PVP | 60 | 2.00 |
| Purified water | 600 | — |
| Magnesium stearate | 30 | 1.00 |
| It is total | 3000 | 100 |
Remarks：Water vapors away when finally being dried as solvent, is not counted in composition, therefore not counts.
2nd, preparation technology
1) each composition is weighed according to prescription, takes beta-schardinger dextrin to be dissolved in appropriate 60 DEG C of purified waters, beta-schardinger dextrin is reached full
And concentration, solution maintain 60 DEG C of lasting stirrings, are added dropwise to the ethanol solution of butylphenyl phthaleine while stirring, it is molten to add butylphenyl phthaleine ethanol
After liquid, lasting stirring inclusion 4-5h, 0-4 DEG C of cool overnight, filtering, solid is collected, dry, pulverize, it is standby.
2) take recipe quantity Darapladib, butylbenzene phthalein cyclodextrin inclusion compound, microcrystalline cellulose, lactose, mannitol mixing equal
It is even, it is standby.
3) take recipe quantity PVP to be dissolved in appropriate purified water and the PVP aqueous solution is made, it is standby.
4) using the PVP aqueous solution as adhesive, softwood is prepared, the granulation of 20 mesh sieves, drying, 18 mesh sieve whole grains, is added hard
Fatty acid magnesium is well mixed, filling by Darapladib 80mg/ grains, butylphenyl phthaleine 100mg/ bags.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is aobvious and easy to those skilled in the art
See.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, application claims guarantor is belonged to
The scope of shield.
Claims (2)
1. the pharmaceutical composition of the inhibitor containing lipoprotein-associated phospholipase A_2, it is characterised in that the pharmaceutical composition is by fat egg
It is a kind of according to weight ratio composition in white correlation PLA 2 inhibitors and following component：Fenofibrate or PSS,
Wherein：
The weight of lipoprotein-associated phospholipase A_2 inhibitor and fenofibrate ratio 1：1-1：7；
The weight of lipoprotein-associated phospholipase A_2 inhibitor and PSS ratio 1：1.5-1：2；
The lipoprotein-associated phospholipase A_2 inhibitor is Darapladib.
2. a kind of pharmaceutical preparation, it contains the medicine group of the inhibitor containing lipoprotein-associated phospholipase A_2 described in claim 1
Compound and pharmaceutically acceptable carrier；The preparation be tablet, capsule, parenteral solution, granule, slow-release pill, preparation capable of permeating skin,
Gel, film, emulsion；The pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, selected from filler,
One in adhesive, disintegrant, lubricant, solubilizer, suspending agent, wetting agent, pigment, solvent, surfactant or flavouring
Kind is several；The filler is selected from starch, pregelatinized starch, dextrin, glucose, sucrose, lactose, lactitol, microcrystalline cellulose
Element, mannitol, sorbierite or xylitol；The disintegrant is selected from Ac-Di-Sol, PVPP, low substitution hydroxyl
Propyl cellulose, sodium carboxymethyl starch or starch；The lubricant be selected from magnesium stearate, talcum powder, superfine silica gel powder, PEG4000,
PEG6000 or sldium lauryl sulfate；Described adhesive be selected from sodium carboxymethylcellulose, HPMC, ethyl cellulose,
PVP, starch slurry, sucrose, Icing Sugar, gelatin or polyethylene glycol；The solubilizer is selected from 1B, L-arginine；It is described to help
Suspension is selected from superfine silica gel powder, beeswax, cellulose or solid polyethylene glycol；The wetting agent is selected from glycerine, Tween-80, ethyoxyl
Rilanit special or lecithin；The solvent be selected from ethanol, liquid polyethylene glycol, isopropanol, Tween-80, glycerine, propane diols or
Vegetable oil, the vegetable oil are selected from soybean oil, castor oil, peanut oil, ready-mixed oil；The surfactant is selected from detergent alkylate
Sodium sulfonate, stearic acid, Pluronic F68, fatty acid sorbitan or polysorbate；The flavouring be selected from Ah
This Ba Tian, Sucralose, essence, Steviosin, acesulfame potassium, citric acid or saccharin sodium.
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| CN108310371B (en) * | 2018-03-09 | 2020-06-09 | 广州铭康生物工程有限公司 | Blood fat reducing pharmaceutical composition and application thereof |
| CN109966288A (en) * | 2019-05-05 | 2019-07-05 | 嘉兴市第二医院 | A kind for the treatment of or prevention atherosclerosis drug and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358175A (en) * | 1999-05-01 | 2002-07-10 | 史密丝克莱恩比彻姆有限公司 | Pyrimidinone compounds |
| CN1418199A (en) * | 2000-02-16 | 2003-05-14 | 史密斯克莱·比奇曼公司 | Pyrimidine-4-one derivatives as LDL-PLA2 inhibitors |
| CN1479724A (en) * | 2000-10-10 | 2004-03-03 | ʷ��˿�������ȳ�ķ����˾ | Pyridione derivatives for tretment of atherosclerosis |
-
2015
- 2015-05-26 CN CN201510273876.8A patent/CN104840963B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1358175A (en) * | 1999-05-01 | 2002-07-10 | 史密丝克莱恩比彻姆有限公司 | Pyrimidinone compounds |
| CN1418199A (en) * | 2000-02-16 | 2003-05-14 | 史密斯克莱·比奇曼公司 | Pyrimidine-4-one derivatives as LDL-PLA2 inhibitors |
| CN1479724A (en) * | 2000-10-10 | 2004-03-03 | ʷ��˿�������ȳ�ķ����˾ | Pyridione derivatives for tretment of atherosclerosis |
Non-Patent Citations (2)
| Title |
|---|
| Darapladib: an emerging therapy for atherosclerosis;Marshall A. Corson;《Therapeutic Advances in Cardiovascular Disease》;20101231;第4卷(第4期);第241-248页 * |
| 脂蛋白在动脉粥样硬化发病中的分子机制及其干预;陈雅琴等;《中国动脉硬化杂志》;20091231;第17卷(第2期);第166-168页 * |
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