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CN1582928A - Medicinal composition and its use in treatment of diabetes - Google Patents

Medicinal composition and its use in treatment of diabetes Download PDF

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Publication number
CN1582928A
CN1582928A CN 200410019483 CN200410019483A CN1582928A CN 1582928 A CN1582928 A CN 1582928A CN 200410019483 CN200410019483 CN 200410019483 CN 200410019483 A CN200410019483 A CN 200410019483A CN 1582928 A CN1582928 A CN 1582928A
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China
Prior art keywords
pioglitazone
metformin
compound
diabetes
administration
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CN 200410019483
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CN1327840C (en
Inventor
王杏林
徐维钰
张宗鹏
陈学民
郑家通
田义红
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Jiangsu Deyuan Pharmaceutical Co ltd
Tianjin Institute of Pharmaceutical Research Co Ltd
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Lianyungang Deyuan Pharmaceutical Co Ltd
Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

A composite medicine for preventing and treating diabetes and the diseases associated with diabetes is prepared from pirolione or its pharmacologically acceptable salt, fluamine or its pharmacologically acceptable salt, and one or more pharmacologically acceptable carrier.

Description

A kind of pharmaceutical composition and be used for the treatment of application in the diabetes in preparation
Technical field
The invention belongs to treatment diabetes medicament field, more particularly relate to the pharmaceutical composition of a kind of pioglitazone and metformin, and said composition preparation be used for the treatment of and/or prevent diabetes, with diabetes diseases associated and some complication thereof in application.
Background technology
Diabetes are one group of clinical syndromes that caused by the h and E factor interaction.Estimate that according to Epidemiological study present global diabetics sum has exceeded 100,000,000, wherein about 90% is type ii diabetes, its pathogeny is that insulin resistant is main, is main with defect of insulin secretion or defect of insulin secretion, and companion's insulin resistant and liver glucose produce to be increased.The type ii diabetes patient is often with diseases such as obesity, hypertension, hyperlipemia, fatty liver and coronary heart disease.
United States Patent (USP) discloses biguanides antihyperglycemic metformin No. 3174901, and the auxiliary mechanism of its blood sugar control is to suppress liver to produce glucose and increase the periphery ingestion of glucose, reduces insulin resistance thus.
The clear 61-267580 of Japan Patent, European patent Ep193256, U.S. Pat 4687777 discloses the hyperglycemia of thiazolidinediones euglycemic agent pioglitazone and has regulated the lipid metabolism effect, its mechanism of action exists relevant with insulin, can reduce the insulin resistance of peripheral tissues and liver, increase the glucose that relies on insulin and handle, and reduce the output of glycogen.Following document discloses the example of pioglitazone and metformin use in conjunction: Pioglitazonehydrochloride in combination with metformin in the treatment of type 2 diabetesmellitus:a randomized such as (1) Einhorn D, placebo-controlled study.Clin Ther.2000Dec; 22 (12): 1395-409. discloses when using the metformin poor blood glucose control separately, with the therapeutic effect and the toleration of pioglitazone hydrochloride use in conjunction.
(2) Effects of combined pioglitazone and metformin on diabetes andobesity in Wistar fatty rats. Clin Exp Pharmacol Physiol. 2002 Apr such as Suzuki M; 29 (4): 269-74. discloses pioglitazone hydrochloride and metformin hydrochloride use in conjunction, to the therapeutic effect of the Wistar obese rat of hyperglycemia, hyperglyceridemia, hyperketonemia.
Hypoglycemic effect and safety when (3) Pan Changyu etc. discloses pioglitazone hydrochloride and sulphanylureas or biguanides use in conjunction in " effectiveness of metformin hydrochloride treatment type ii diabetes and the multiple center clinical study of safety ".
Pioglitazone is a kind of thiazolidone para-insulin opposing improving agent, reduces insulin resistant, protection β cell function, and sugar, the fat that can effectively treat the noninsulindependent diabetes obese patient are unusual.Metformin now has been widely accepted and has been light, moderate diabetes mellitus type obese patient's first-selected hyperglycemia medicine particularly.Even, intervention effect is also arranged for the interstage-IGT (glucose tolerance attenuating) of type ii diabetes, can stop or delay to enter the diabetes stage by the IGT state.
Insulin resistant is the major defect of type ii diabetes starting stage.Insulin resistant is through the generation of type ii diabetes, the development overall process, and thiazolidinediones pioglitazone hydrochloride and metformin all tool reduce the insulin resistant effect, but the mechanism of action difference of the two, the site of action of the two also has difference, pioglitazone mainly promotes peripheral tissues's (skeletal muscle) ingestion of glucose, the insulin resistance that can be used for type ii diabetes, and metformin mainly suppresses hepatic glucose output, so the two share, effect concentrates on metabolic deficiency, the anti-diabetic effect can be strengthened, and helps to use more separately metformin to reach better blood sugar control.
Summary of the invention
Now, there is wonderful reality to show, the combination medicine form of pioglitazone and metformin can provide useful especially glycemic control effect and not observe side effect, observed synergism is hypoglycemic remarkable improvement, therefore this combination medicine form is particularly useful for treating diabetes, especially II type sugar sick and with the diabetes diseases associated.
Therefore, the invention provides a kind of mammal such as people's treatment of diabetes method, this method comprises euglycemic agent such as pioglitazone or its pharmaceutically acceptable salt of effective, the nontoxic and pharmaceutically acceptable amount of the mammal that needs this treatment, pharmaceutical composition with biguanides antihyperglycemic agents such as metformin or its pharmaceutically acceptable salt, wherein, the consumption of pioglitazone or its pharmaceutically acceptable salt is 5-60mg, and the consumption of metformin or its pharmaceutically acceptable salt is for being no more than 3000mg.
Should be appreciated that pioglitazone and metformin be respectively with its pharmaceutically acceptable form as suitable related drugs active agent delivery, comprise its pharmaceutically acceptable derivates such as pharmaceutically acceptable salt, ester and solvate.Should be understood that all pharmaceutically acceptable forms that the present invention includes activating agent itself.The suitable pharmaceutically acceptable form of metformin is an acid-addition salts, example hydrochloric acid salt, acetate, benzoate, mesylate, maleate etc., yet, preferably use metformin itself or its hydrochlorate.Obtain the officinal salt of metformin by metformin and corresponding acid reaction with reference to the US3174901 method.
The pharmaceutically acceptable salt that pioglitazone is suitable comprises hydrochlorate, formates, fumarate, acetate, benzoate, mesylate, sulfate, maleate etc., yet, preferably use pioglitazone itself or its hydrochlorate.The officinal salt that can prepare pioglitazone with reference to the EP193256 method.
A particular aspects, this method comprises and gives 5～60mg pioglitazone or pioglitazone hydrochloride, especially when the every day administration.
Particularly, this method comprise give 5～15,15～30,30～45 every day, 45～60mg pioglitazone or pioglitazone hydrochloride.
Particularly, this method comprises and gives 5～15mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 15～30mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 30～45mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 45～60mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 5mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 10mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 15mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 30mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 45mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 60mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
A particular aspects, this method comprises metformin or the metformin hydrochloride that is no more than 3000mg, especially when the every day administration.Particularly preferably be, the consumption of metformin or metformin hydrochloride is 250mg, 750mg, 1000mg, especially when the every day administration.
The invention solves diabetics needs long-term worry of repeatedly taking medicine, and by making the compound preparation of different proportionings, improves medicining mode, has reduced medicining times, once a day, makes things convenient for the patient to take for a long time.
On the other hand, the invention provides a kind of pioglitazone and metformin preparation be used for the treatment of and/or prevent diabetes, with the diabetes diseases associated, and the application in some complication, particularly, the treatment diabetes especially type ii diabetes and with the method for diabetes diseases associated in application.This method comprises pioglitazone and metformin administration simultaneously.Administration simultaneously comprises the preparation that gives pioglitazone and metformin, perhaps with the independent preparation while administration basically of every kind of activating agent.
Confirm that through vast amount of clinical if type ii diabetes is diagnosed in back 3 years only with a kind of medicine treatment, glucose control progressivity descends, and has two medicine therapeutic alliances of complementary action often to be used to obtain the maximum therapy effect and to reduce side effect.Pioglitazone and metformin two medicine use in conjunction not only effectively blood sugar control, reduce insulin resistant, protection β cell function, reduced hypoglycemic incidence rate simultaneously, played synergism.Two medicine use in conjunction can delay and stop advancing of disease, and the long-term complications of prevent diabetes is as heart disease, blind, amputation and renal failure.
Term used herein " with the diabetes diseases associated " comprise those diseases relevant with the prediabetes state, with diabetes self diseases associated and with the diabetes complications associated with arterial system.
Term used herein " those diseases relevant with the prediabetes state " comprises such as insulin resistance disease, comprises that heritability insulin resistant, glucose tolerance weaken and hyperinsulinemia.
Term used herein " with diabetes self diseases associated " comprises hyperglycemia, and insulin resistant comprises insulin resistant and the obesity day after tomorrow.Other and diabetes diseases associated comprise hypertension and cardiovascular disease, especially atherosclerosis and with the insulin diseases associated.Comprise polycystic ovary syndrome and inductive insulin resistant of steroid and gestational diabetes with the insulin diseases associated.
" with the diabetes complications associated with arterial system " comprises kidney disease, especially relevant with type ii diabetes kidney disease, neuropathy and retinopathy.
The kidney disease relevant with type ii diabetes comprises nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and late period kidney disease.
Term used herein " pharmaceutically acceptable " comprises any veterinary purpose: for example term " pharmaceutically acceptable " comprises veterinarily acceptable chemical compound.
Useful especially glycemic control effect by the present invention's treatment provides is designated as the synergism with respect to contrast, and this contrast is contemplated to the effect summation of independent active agents.
One preferred aspect, when treatment and when using according to the present invention, the dosage level of used various activating agents will less than reach add merely and the glycemic control effect dosage that may need.
On the one hand, the invention provides a kind of pharmaceutical composition that contains pioglitazone and metformin again.Said composition contains 5～60mg pioglitazone or pioglitazone hydrochloride and is no more than 3000mg, metformin or metformin hydrochloride and one or more pharmaceutically acceptable carrier.
Usually said composition is suitable for oral administration, and still, they also are fit to other administering mode, for example parenteral, sublingual administration or percutaneous dosing.
In order to reach the concordance of administration, the present composition is preferably single agent form.
The single agent representation that is used for oral administration can be tablet and capsule, can contain following excipient such as filler, lactose, sucrose, starch, microcrystalline Cellulose, sorbitol, calcium phosphate; Binding agent, for example syrup, gelatin, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, starch, dextrin; Disintegrating agent, for example microcrystalline Cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone; Lubricant, for example magnesium stearate; High-molecular bone frame material, for example hydroxypropyl emthylcellulose, hydroxypropyl cellulose, ethyl cellulose, Brazil wax, hydrogenated vegetable oil, acrylic resin; Filmogen, for example hydroxypropyl emthylcellulose, polyvinylpyrrolidone, acrylic resin etc.
The preparation method of preferred pharmaceutical composition of the present invention, can be made into the double-layer tablet up and down that contains 5～60mg rapid release pioglitazone or its pharmaceutical salts and be no more than 3000mg SRM or its pharmaceutical salts, or can be made into internal layer for being no more than 3000mg SRM or its pharmaceutical salts, outer for containing the pioglitazone of 5～60mg rapid release or the double-layer tablet of its pharmaceutical salts.
Metformin or its pharmaceutical salts are made the slow releasing tablet that only need take every day once among the present invention, can slowly discharge in vivo, it is steady to keep blood drug level, half-life prolongs, safety, efficient, low toxicity, taking convenience, and side effect and incompatibility are less, and convenient and pioglitazone or its pharmaceutical salts are made the compound preparation of different proportionings, and patient's taking convenience is difficult for missing, and has increased the obedient type of medication.
These compositionss are preferably to make unit dosage forms with the amount that relevant daily dose suits.
The unit dose of suitable pioglitazone comprises 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44, the 45mg pioglitazone.
Compositions of the present invention can administration every day 1～3 time, but preferred administration every day 1 or 2 times.
The pioglitazone given dose is 5mg/ days, 10mg/ days, and 15mg/ days, 30mg/ days, 45mg/ days, 60mg/ days.
The metformin proper dosage comprises and is no more than 3000mg every day, and preferably with the unit dose administration of 250mg, 500mg, 1000mg, 1500mg or 2000mg, an example of metformin dosage is each 1000mg, once a day.
The unit dose that pioglitazone and metformin are suitable also comprises the known dose of these chemical compounds, as describing among handbook Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia and PHYSICINS ' the DESK REFERENCE or mentioning.
Below by acute, the toxicity test of pharmacology, pharmacokinetics is tested, and pharmacodynamic experiment is further set forth the present invention.
One, compound metformin/pioglitazone acute toxicity test:
1, test objective:
Mice produces after different proportioning (500: 7.5,500: 15,500: 30) the single oral administrations of observation compound metformin/pioglitazone acute toxic reaction and dead distribution situation are calculated LD 50Value.For pharmacodynamics test, repeatedly the compound recipe proportioning of the toxicity test of repetitively administered and dosage design and clinical safety provide reference.
2, experiment material:
(1) laboratory animal
Kunming mouse, male and female half and half, body weight 18-22g.Laboratory Animal Facility: secondary; The quality certification number: accurate No. 012 of the real moving facility in Tianjin; The laboratory animal quality certification: No. the 001st, the accurate word of the real kinoplaszm R in W-J Tianjin.Experimental situation and condition: 22 ± 4 ℃ of room temperatures, humidity 60 ± 20%.The central air-conditioning automatic ventilation.Illumination 12 hours.Freely ingest and drinking public water supply.Change water every day once.
(2) experiment medicine
Compound metformin/pioglitazone, medicine are mixed with the suspendible medicinal liquid of 100mg/ml with 1%CMC.
3, experimental technique and result:
(1) experimental technique:
50 of Kunming mouses, male and female half and half are divided into 5 groups at random by sex, are respectively 5000,4000,3200,2560, five dosage groups of 2048mg/kg.Animal fasting administration in 6 hours.Medicine is mixed with the medicinal liquid of 100mg/ml with the 1%CMC suspendible, adopts the not isopyknic mode administration of isoconcentration, the administration volume is respectively 0.50,0.40,0.32,0.26,0.20ml/10g.Observe toxic reaction and the time of origin thereof of animal behind the medicine, death condition and time, dead animal carries out anatomical examination, carries out histological examination in case of necessity; Surviving animals was observed 14 days continuously, weighed at 0,1,3,7,14 day that tests, and at the 14th day the part surviving animals was carried out anatomic observation.Statistics animal dead situation, the variation of calculating median lethal dose(LD 50) and the weight of animals.
(2) experimental result:
Compound metformin/pioglitazone (500: 7.5) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 7.5), animal appearance activity in 10-30 minute reduces behind the medicine, part animal occur closing one's eyes (1-6/10); Behind the medicine 1 hour, diarrhoea appearred in 5 animals; Behind the medicine 2 hours, diarrhoea appearred in 10 animals.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 5 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (6), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3137.3mg/kg.(the results are shown in Table 1,2).
Table 1. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 7.5) to the surviving animals body weight
Dosage (mg/kg) 0d 1d 3d 7d 14d
5000???????????19.8±0.9
4000???????????19.9±1.0????20.8±2.5???23.0±2.8??26.5±3.5??29.3±3.9
3200???????????19.8±1.1????21.0±1.2???23.4±1.5??25.6±1.7??28.8±1.8
2560?????????19.9±1.0????20.6±1.1???22.3±1.2??24.8±1.6??28.6±2.3
2048?????????19.7±1.1????20.9±1.4???23.1±1.9??26.1±2.2??29.2±2.7
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 2 for each group surviving animals number.
Table 2. mice single oral gives compound metformin/pioglitazone (500: 7.5) LD 50Measurement result
The only dead general mortality rate LD of the dead death of dosage number of animals 50(mg/kg)
(mg/kg) (only) number (♂) number (♀) is counted (only) (%) (95% fiducial limit)
5000?????10??????5?????????5?????????10????????100
4000?????10??????3?????????5?????????8?????????80
3137.3
3200?????10??????3?????????3?????????6?????????60
(2834.9-3472.1)
2560?????10??????1?????????1?????????2?????????20
2048?????10??????0?????????0?????????0?????????0
Compound metformin/pioglitazone (500: 15) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 15), animal appearance activity in 10-30 minute reduces behind the medicine, part animal occur closing one's eyes (1-4/10); Behind the medicine 1 hour, diarrhoea, myasthenia of limbs behind 1 animal, instability of gait appearred in 3 animals; Behind the medicine 2 hours, diarrhoea appearred in 9 animals, and 1 animal is dying.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 4 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (4), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3348.8mg/kg.(the results are shown in Table 3,4).
Table 3. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 15) to the surviving animals body weight
Dosage (mg/kg) 0d 1d 3d 7d 14d
5000?????????19.7±0.9
4000?????????19.6±1.1????20.3±1.0????22.3±1.0???26.0±1.3???29.0±2.6
3200?????????19.5±1.0????21.1±1.3????23.4±1.1???26.8±1.9???29.7±2.5
2560????????19.7±1.0????21.2±1.2????22.8±1.7????26.2±1.8????29.8±2.0
2048????????19.7±1.0????21.1±1.1????23.4±1.3????26.7±1.6????29.8±2.3
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 4 for each group surviving animals number.
Table 4. mice single oral gives compound metformin/pioglitazone (500: 15) LD 50Measurement result
The only dead general mortality rate LD of the dead death of dosage number of animals 50(mg/kg)
(mg/kg) (only) number (♂) number (♀) is counted (only) (%) (95% fiducial limit)
5000???????10??????5???????5???????10????????100
4000???????10??????3???????4???????7?????????70
3348.8
3200???????10??????3???????2???????5?????????50
(3029.6-3701.7)
2560???????10??????0???????1???????1?????????10
2048???????10??????0???????0???????0?????????0
Compound metformin/pioglitazone (500: 30) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 30), 10-30 minute animal activity reduces behind the medicine, part animal close one's eyes (1-4/10); Behind the medicine 1 hour, 4 animals diarrhoea; Behind the medicine 2 hours, 1 animal instability of gait, 7 animals diarrhoea.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 5 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (10), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3726.7mg/kg.(the results are shown in Table 5,6).
Table 5. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 30) to the surviving animals body weight
Dosage (mg/kg) 0d 1d 3d 7d 14d
5000???????????20.3±1.0
4000???????????20.2±1.1??21.3±1.2??22.8±1.2??25.2±1.3??28.8±1.8
3200???????????20.4±0.9??21.9±1.6??23.5±2.0??26.2±2.6??28.5±2.4
2560????20.3±0.9??22.0±0.5??24.1±1.7??26.6±2.3??29.7±2.6
2048????20.2±1.1??21.9±0.9??23.8±1.0??26.7±1.4??29.6±2.5
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 6 for each group surviving animals number.
Table 6. mice single oral gives compound metformin/pioglitazone (500: 30) LD 50Measurement result
The only dead general mortality rate LD of the dead death of dosage number of animals 50(mg/kg)
(mg/kg) (only) number (♂) number (♀) is counted (only) (%) (95% fiducial limit)
5000???????10??????5?????????5?????????10???????100
4000???????10??????3?????????1?????????4????????40
3726.7
3200???????10??????2?????????1?????????3????????30
(3338.6-4159.8)
2560???????10??????0?????????1?????????1????????10
2048???????10??????0?????????0?????????0????????0
4, conclusion:
The mice single oral gives the toxic reaction basically identical of compound metformin/pioglitazone appearance of three kinds of proportionings, 10-30 minute part animal activity reduces, closes one's eyes after the administration, 1 hour part animal diarrhoea, instability of gait behind the medicine, the number of animals that toxic reaction takes place and the order of severity and dosage are proportionate.Animal dead appears at behind the medicine 4-5 hour the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal, other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of the different proportionings of mice orally give compound metformin/pioglitazone (500: 7.5,500: 15,500: 30) is respectively 3137.3,3348.8,3726.7mg/kg.
Two, the pharmacokinetic of compound metformin/pioglitazone blood sugar lowering:
Compound antihypelipidemic is the compound preparation of biguanides antidiabetic drug metformin and Thiazolidine ketone antidiabetic drug pioglitazone, and (500: 30, w/w), because mechanism of action difference, compatibility was in the hope of reaching better hypoglycemic effect to be called for short compound antihypelipidemic.This test is intended to illustrate the similarities and differences that absorb between compound preparation and the single preparations of ephedrine by the absorption test of rat.
1, material
(1) medicine:
Metformin: face with preceding and become 15mg/ml with water dissolution, the administration capacity is the 1ml/100g body weight, is equivalent to 150mg/kg.
Pioglitazone: face with preceding and become 0.9mg/ml with the 1%CMCNa suspendible, the administration capacity is the 1ml/100g body weight, is equivalent to 9mg/kg.
Compound antihypelipidemic: face with preceding and become 15mg metformin and 0.9mg pioglitazone/ml with the 1%CMCNa suspendible, the administration capacity is the 1ml/100g body weight, is equivalent to 150mg/kg metformin and 9mg/kg pioglitazone.
(2) reagent:
Methanol: top grade is pure, Tianjin Concord Technology Co., Ltd.'s product, lot number 031204.Potassium dihydrogen phosphate: AR, Red Star chemical plant, Beijing product, lot number 851011-1.B7: Tianjin chemical reagent two factory's products.Acetonitrile: AR, Tianjin Concord Technology Co., Ltd.'s product, lot number 031015.Sodium acetate: Tianjin Bazhou City's chemical industry subsidiary factory of quartzy Clock Factory product, lot number 980303.
(3) instrument:
NL-200TPA analytical balance: day island proper Tianjin company.
TGL-16C high speed tabletop centrifuge: Anting Scientific Instrument Factory, Shanghai.
HPLC:WATERS 515 pumps; 717 automatic samplers; The RAININ UV-detector;
ANASTAR chromatographic data work station.
(4) animal:
Healthy Wistar rat, female, the about 210g of body weight, the Laboratory Animal Facility quality certification " accurate No. 013 of Tianjin Laboratory Animal Facility " is issued by Tianjin management of laboratory animal committee, meets primary standard.The normal raising after three days for examination.
2, method:
(1) sample collecting and processing:
12 of healthy Wistar rats, female, fasting 16 hours is divided into three groups by weight average, and promptly pioglitazone 9mg/kg organizes, metformin 150mg/kg group and compound antihypelipidemic group.In 8:00 in morning oral administration gavage said medicine respectively, behind medicine 0.33,0.66,1.0,1.5,2.0,4.0,6.0,12.0,24.0 and 36.0 hours eye socket blood sampling 0.5ml respectively, centrifugalize serum.
Quantitatively draw the serum 50 μ l of metformin group and compound antihypelipidemic treated animal, add equal-volume 10% perchloric acid, the shake well protein precipitation, centrifugal, supernatant 20 μ l sample introductions, HPLC analyzes.Manage operation preparation standard serum sample again with blank serum, concentration is respectively 0,0.5,1,2,5,10 and 20 μ g/ml, and as standard curve, processing method is the same.
Quantitatively draw the serum 150 μ l of pioglitazone group and compound antihypelipidemic treated animal, add the 1ml dichloromethane, shake well, centrifugal, get 800 μ l lower floor organic faciess and place another centrifuge tube, air blow drying, 75 μ l mobile phases are redissolved, centrifugal 20 μ l sample introductions, and HPLC analyzes.Manage operation preparation standard serum sample again with blank serum, concentration is respectively 0,0.1,0.5,1,5 and 10 μ g/ml, and as standard curve, processing method is the same.
(2) chromatographic condition:
Metformin: immobile phase: C 18The ODS post, 4.6 * 250mm, 10 μ, post 22I25117
Mobile phase: methanol: 0.005M potassium dihydrogen phosphate (pH2.5)=10: 90
Column temperature: 40 ℃
UV detects: 233nm
Pioglitazone: immobile phase: C 18The ODS post, 4.6 * 100mm, 5 μ, post 22K10040
Mobile phase: acetonitrile: 0.1M sodium acetate (pH4.5)=39: 61
Column temperature: 30 ℃
UV detects: 269nm
(3) result:
Metformin:
The linear equation of serum standard curve (0～20 μ g/ml) is: C=0.0000353A+0.10355 (r=0.9992).The response rate is 95.04%.The blood drug level of different time sees Table 7 behind rat oral administration of metformin and the compound antihypelipidemic, and curve is seen Fig. 1 during medicine; The average out to peak time was respectively 1.1 and 1.0 hours; Peak concentration is respectively 19.6 and 20.4 μ g/ml; AUC is respectively 239.8 and 249.9 μ gh/ml.Compound recipe is 101.7% with respect to the bioavailability of folk prescription.
The blood drug level of different time behind table 7. rat oral administration of metformin and the compound antihypelipidemic
Group through the time blood drug level (μ g/ml)
0.33????0.67????1????1.5????2????4????6????8????12????24????36h
The folk prescription metformin
1????13.5??16.3??19.3??19.3??16.1??8.3???8.2??6.7??6.0???3.1???3.5
2????12.2??15.1??24.6??20.0??16.9??9.3???5.5??5.4??10.4??13.1??2.3
3????14.5??13.7??14.5??18.4??13.7??10.8??5.8??5.2??5.6???4.6???2.8
4????13.6??15.3??16.3??14.0??14.9??7.2???5.1??4.9??4.7???5.4???1.9
mean?13.4??15.1??18.7??17.9??15.4??8.9???6.2??5.5??6.7???6.6???2.6
Compound antihypelipidemic
1????12.6??19.6??27.2??21.6??14.9??14.7??8.5??7.3??6.8???6.6??2.5
2????12.5??15.6??16.3??15.1??15.9??10.2??6.9??6.5??6.5???5.7??2.9
3????11.6??18.7??19.1??16.1??16.2??10.7??7.3??6.3??5.3???4.3??2.6
4????15.9??17.9??19.1??15.4??18.8??10.3??8.0??6.8??6.7???6.8??3.4
mean?13.1??18.0??20.4??17.1??16.4??11.5??7.7??6.7??6.3???5.8??2.8
Pioglitazone:
The linear equation of serum standard curve (0～10 μ g/ml) is: C=0.0000310A-0.1488 (r=0.9988).The response rate is 71.7%.The blood drug level of different time sees Table 8 behind oral pioglitazone of rat and the compound antihypelipidemic, and curve is seen Fig. 2 during medicine; The average out to peak time was respectively 4.0 and 3.9 hours; Peak concentration is respectively 6.8 and 5.3 μ g/ml; AUC is respectively 80.4 and 85.0 μ gh/ml.Compound recipe is 105.7% with respect to the bioavailability of folk prescription.
The blood drug level of different time behind oral pioglitazone of table 8. rat and the compound antihypelipidemic
Group through the time blood drug level (μ g/ml)
0.33????0.67????1???????1.5?????2??????4???????6???????8???????12???????24?????36h
The folk prescription pioglitazone
1?????0.68????2.95????3.49????5.32????3.71???4.72????4.36????4.13????2.48????0.36????nd
2?????5.84????10.81???8.09????10.73???7.60???7.32????5.90????5.12????3.25????0.66????0.34
3?????3.51????2.84????3.62????3.96????4.85???4.47????4.93????4.07????3.10????0.69????0.42
4?????0.81????2.36????3.00????3.23????3.74???4.54????6.06????6.14????3.57????0.39????nd
mean??2.71????4.74????4.55????5.81????4.97???5.26????5.31????4.87????3.10????0.52????0.38
Compound antihypelipidemic
1?????1.05????2.29????2.80????2.87????2.85???3.26????2.38????1.86????1.12????2.58????0.40
2?????0.42????0.46????3.16????3.81????3.19???5.49????5.95????5.09????3.41????1.73????2.47
3????0.44???3.37???4.21???5.41???5.48???5.95???5.09???3.40???1.68???2.44???0.69
4????3.33???4.21???5.41???5.93???4.57???3.64???5.28???3.22???1.85???0.80???1.31
mean?1.31???2.58???3.90???4.51???4.02???4.59???4.67???3.39???2.01???1.89???1.22
3, conclusion:
The average out to peak time was respectively 1.1 and 1.0 hours behind rat oral administration folk prescription metformin and the compound antihypelipidemic; Peak concentration is respectively 19.6 and 20.4 μ g/ml; AUC is respectively 239.8 and 249.9 μ gh/ml.Compound recipe is 101.7% with respect to the bioavailability of folk prescription.Average out to peak time behind oral pioglitazone of rat and the compound antihypelipidemic was respectively 4.0 and 3.9 hours; Peak concentration is respectively 6.8 and 5.3 μ g/ml; AUC is respectively 80.4 and 85.0 μ gh/ml.Compound recipe is 105.7% with respect to the bioavailability of folk prescription.The interior absorption of the rat body of two kinds of antidiabetic drugs that comprised in the compound antihypelipidemic is noiseless substantially, with the folk prescription there was no significant difference.
Description of drawings
Fig. 1 is curve during medicine behind rat oral administration metformin and the compound preparation;
Fig. 2 is curve during medicine after rat oral administration pioglitazone and the compound preparation administration.
Three, compound metformin/Pioglitazone pharmacodynamics test:
1. experiment material
1.1 animal used as test:
The Wistar rat, body weight 140-160g. The animal used as test quality certification: No. the 001st, the accurate word of the real kinoplaszm R in W-J Tianjin.
1.2 experimental situation and condition
The Laboratory Animal Facility secondary, the quality certification number: accurate No. 012 of the real moving facility in Tianjin; 22 ± 4 ℃ of room temperatures, humidity 60 ± 20%. The central air-conditioning automatic ventilation. Illumination 12 hours. Freely ingest and drinking public water supply. Change water every day once.
1.3 medicine:
Metformin hydrochloride; PIOGITAZONE HYDROCHLORIDE. Behind two medicine grind into powder mixings, be mixed with suspension with 1%CMC.
1.4 reagent and instrument:
Streptozotocin (Streptozotocin, STZ), Sigma, S-0130, the import packing, Beijing is glad to be provided through biotech company of section. Specification: 1g/ bottle. Purity: 98%.
Capital of a country blood glucose meter (SUPER GLUCOCARD II) and test strip, Japan produces, and Maibang Biological Engineering Technology Co., Beijing provides.
The insulin kit: Tianjin Shu Pu biotechnology company provides. Lot number: 06043-A SUNRISE remote control ELIASA, TECAN product.
2. experimental technique and result
The Wistar rat, male, 300,140g-160g, fasting 16hr, the STZ of lumbar injection 30mg/kg (is dissolved in the citrate buffer solution of the pH value 4.4 of 0.1mol/L in 4 ℃ of ice baths, use immediately after joining), every day 1 time, continuous 3 times, administration was fed with high-sugar-fat-diet (basal feed 55%, lard 25% after 2 weeks, sucrose 20%), survey rat FBG (fasting 12h before surveying) after feeding for 6 weeks, select 64 of the rats of FBG 〉=12.0mmol/L, be divided at random 8 groups, every group 8, be made as respectively 300: 1.5 groups of model control group and compounds, 300: 3 groups of compounds, 300: 4.5 groups of compounds, 300: 6 groups of compounds, 300: 6.75 groups of compounds, 300: 9 groups of compounds, 300: 27 groups of compounds. Other get 8 normal male Wistar rats (with above-mentioned rat with batch getting, FBG≤5.0mmol/L) as the physiology control group. Physiology contrast and model control group gavage give 1%CMC, and 7 compound groups successively gavage give 300mg: the compound medicine of 1.5mg/kg, 300mg: 3mg/kg, 300mg: 4.5mg/kg, 300mg: 6mg/kg, 300mg: 6.75mg/kg, 300mg: 9mg/kg, 300mg: 27mg/kg (Metformin hydrochloride: PIOGITAZONE HYDROCHLORIDE). Tested medicine is mixed with the suspension of variable concentrations with 1%CMC, i.g administration in morning every day, the administration volume is 1ml/100g, and physiology contrast and model control group gavage give isopyknic 1%CMC. Successive administration 21d, 22d 9:00 in morning gets 1 of blood (getting the front fasting 12h of blood) with glass capillary from the eyeground vein clump, surveys FBG with blood-sugar detecting instrument, and other gets blood 1ml, centrifuging and taking serum is pressed the kit illustration method and is adopted the ELASE method to survey Diagnostic Value of Fasting Serum insulin (FINS). Calculate: hypoglycemic absolute value before and after the administration (FBG before hypoglycemic absolute value=administration 21dFBG-administration), hypoglycemic percentage (hypoglycemic percentage=[FBG * 100% before (FBG before the administration 21dFBG-administration)/administration]) and insulin resistance index (IR) (IR=FBG * FINS/22.5). Every data represent that with mean+SD the t check compares between each group and model control group employing group. The result: the FBG of the reduction hyperglycemic rat that the compound medicine of each ratio all can be in various degree, the above dosage of compound 300mg: 3mg/kg and model control group relatively, there were significant differences for hypoglycemic absolute value and hypoglycemic percentage, and certain dosage correlation is arranged; The compound medicine of each ratio all can obviously reduce FINS and the IR level of hyperglycemic rat. See Table 9,10.
Table 9 compound metformin hydrochloride-Pioglitazone is on the impact of rat fasting blood-glucose
FBG administration 21d FBG FBG difference (21d-1d) administration 21d hypoglycemic percentage before the animals administer
Group
(mmol/L) (mmol/L) (%) for number (mmol/L)
Blank 8 3.7 ± 0.5***  3.8±0.5 ***      0.1±0.4           2.7±11.7
Model contrasts 8 20.5 ± 3.9 20.0 ± 3.5-0.5 ± 1.3-2.1 ± 6.0
Compound 300: 1.5 8 20.3 ± 5.2 17.9 ± 3.9-2.4 ± 2.5-10.7 ± 10.1
Compound 300: 38 20.5 ± 4.9 17.6 ± 3.2-2.9 ± 2.4*        -12.8±8.8 *
Compound 300: 4.5 8 20.4 ± 4.3 17.7 ± 4.3-2.7 ± 2.6-13.1 ± 11.5*
Compound 300: 68 20.5 ± 4.2 17.3 ± 6.0-3.2 ± 2.8*        -17.3±16.4 *
Compound 300: 6.75 8 20.3 ± 4.0 16.4 ± 3.0-3.9 ± 2.2**       -18.7±8.5 ***
Compound 300: 98 20.5 ± 5.5 15.9 ± 4.3-4.6 ± 2.3***      -22.5±9.4 ***
Compound 300: 27 8 20.3 ± 3.6 16.2 ± 3.4-4.1 ± 2.5**       -20.0±12.2 **
Annotate: compare with model control group,*p＜0.05， **p＜0.01， ***p＜0.001
Table 10 compound metformin hydrochloride-Pioglitazone is on the impact of rat limosis insulin and insulin resistance
Administration 21dFBG administration 21dFINS administration 21d insulin
The group number of animals
(mmol/L) (mmol/L) opposing index (logarithm)
Blank 8 3.8 ± 0.5***     3.86±0.82 ***     -0.20±0.12 ***
Model contrasts 8 20.0 ± 3.5 32.35 ± 15.93 1.40 ± 0.29
Compound 300: 1.5 8 17.9 ± 3.9 8.80 ± 4.63**      0.79±0.25 ***
Compound 300: 38 17.6 ± 3.2 6.53 ± 4.00**      0.65±0.22 ***
Compound 300: 4.5 8 17.7 ± 4.3 12.68 ± 9.63**     0.87±0.31 **
Compound 300: 68 17.3 ± 6.0 8.27 ± 4.56**      0.70±0.25 ***
Compound 300: 6.75 8 16.4 ± 3.0 7.28 ± 4.04**      0.66±0.25 ***
Compound 300: 98 15.9 ± 4.3 9.18 ± 5.00**      0.72±0.37 ***
Compound 300: 27 8 16.2 ± 3.4 9.64 ± 4.33**      0.79±0.25 ***
Annotate: compare with model control group,*p＜0.05， **p＜0.01， ***p＜0.001
3. experiment conclusion
Compound metformin hydrochloride-Pioglitazone (300mg: 1.5mg/kg, 300mg: 3mg/kg, 300mg: 4.5mg/kg, 300mg: 6mg/kg, 300mg: 6.75mg/kg, 300mg: 9mg/kg, 300mg: 27mg/kg) the continuous gastric infusion 21d of difference, the compound medicine of each ratio all can be in various degree FBG, FINS and the IR level of reduction hyperglycemic rat, especially obvious to the reduction of FINS and IR.
The specific embodiment
The present invention will be further described below in conjunction with embodiment, but these embodiment are not limitation of the present invention.In order to explain enforcement of the present invention more fully, provide following example of formulations.Preparation can adopt the form of any one compositions among the present invention.The different proportioning of elite compound metformin/pioglitazone (1) was representative in 500: 15 (2) 750: 15 (3) 1000: 15.
Preparation 1
Bilayer tablet up and down:
Upper component Consumption/sheet Weight concentration (%)
Pioglitazone hydrochloride ????15mg ????12.1
Microcrystalline Cellulose ????55mg ????44.4
Lactose ????45mg ????36.3
Polyvinylpyrrolidone ????3mg ????2.4
Carboxymethyl starch sodium ????4.5mg ????3.6
Magnesium stearate ????0.5mg ????0.4
Pulvis Talci ????1mg ????0.8
Following composition of layer Consumption/sheet Consumption/sheet Consumption/sheet
Metformin hydrochloride ????500mg ????750mg ????1000mg
Hydroxypropyl emthylcellulose ????190g ????205mg ????210mg
Polyvinylpyrrolidone ????14.0mg ????19.1mg ????24.2mg
Magnesium stearate ????7.1mg ????9.7mg ????12.3mg
Preparation method:
Pioglitazone hydrochloride preparation method of granules: active component, lactose, microcrystalline Cellulose are sieved, and fully mix, mix with above-mentioned powder with polyvinylpyrrolidonesolution solution, sieve, make wet granular in 50-60 ℃ of drying, with carboxymethyl starch sodium, magnesium stearate and Pulvis Talci sieve in advance, join then in the above-mentioned granule.
Metformin hydrochloride preparation method of granules: active component, hydroxypropyl emthylcellulose are sieved, and fully mix, mix with above-mentioned powder with the polyvinylpyrrolidone alcoholic solution, sieve, make wet granular in 50-60 ℃ of drying, add magnesium stearate in above-mentioned granule.
Above-mentioned granule is put double-layer tablet tablet machine tabletting.
Preparation 2
Inside and outside bilayer tablet:
Interior composition of layer Consumption/sheet Consumption/sheet Consumption/sheet
Metformin hydrochloride ????500mg ????750mg ????1000mg
Hydroxypropyl emthylcellulose ????190g ????205mg ????210mg
Polyvinylpyrrolidone ????14.0mg ????19.1mg ????24.2mg
Magnesium stearate ????7.1mg ????9.7mg ????12.3mg
Outer composition of layer Consumption/sheet
Pioglitazone hydrochloride ????15mg
Hydroxypropyl emthylcellulose ????43.6mg
PEG400 ????4.5mg
Preparation method:
Diabecron sustained-release tablet core preparation method: active component, hydroxypropyl emthylcellulose are sieved, and fully mix, mix with above-mentioned powder with the polyvinylpyrrolidone alcoholic solution, sieve, make wet granular in 50-60 ℃ of drying, add magnesium stearate in above-mentioned granule, tabletting.
The pioglitazone hydrochloride coating solution: with pioglitazone hydrochloride and hydroxypropyl emthylcellulose mix homogeneously, get an amount of PEG400 and add in the entry and dissolve, stir down, slowly add said mixture, make into suspension, the coating solution solids content is about 9%.
Suspension is crossed 80 mesh sieves, coating under the suitable condition, and the control gain in weight makes the hydrochloric pioglitazone 15mg of every agreement that contracts a film or TV play to an actor or actress.
Although the present invention has done detailed description in conjunction with its special embodiment, clearly concerning the skilled people in present technique field, still can make various changes and improvements, can not depart from spirit of the present invention and protection domain.

Claims (10)

1, a kind of pioglitazone or its pharmaceutically acceptable salt of containing, drug regimen with metformin or its pharmaceutically acceptable salt, preparation be used for the treatment of and/or prevent diabetes, with diabetes diseases associated and some complication thereof in application, wherein, the consumption of pioglitazone or its pharmaceutically acceptable salt is 5～60mg, and the consumption of metformin or its pharmaceutically acceptable salt is for being no more than 3000mg.
2, according to the application of claim 1, wherein, described pharmaceutically acceptable salt is respectively pioglitazone hydrochloride and metformin hydrochloride.
3, according to the application of claim 1, wherein, the consumption of pioglitazone or its pharmaceutical salts is 5～15,15～30,30～45,45～60mg.
4, according to the application of claim 1, wherein, the consumption of pioglitazone or its pharmaceutical salts is 5mg, 15mg, 30mg, 45mg, 60mg.
5, according to each application among the claim 1-4, wherein, the consumption of metformin or its pharmaceutical salts is 250mg, 750mg or 1000mg.
6, a kind of pharmaceutical composition, said composition contain 5～60mg pioglitazone or its pharmaceutical salts and are no more than 3000mg metformin or its pharmaceutical salts, and one or more pharmaceutically acceptable carrier.
7,, contain 5～15,15～30,30～45 in the said composition, 45～60mg pioglitazone or its pharmaceutical salts according to the compositions of claim 6.
8, according to the compositions of claim 6, said composition contains 5mg, 15mg, 30mg, 45mg, 60mg.Pioglitazone or its pharmaceutical salts.
9,, contain 250mg, 750mg or 1000mg metformin or its pharmaceutical salts in the said composition according to each compositions among the claim 6-8.
10, a kind of preparation of drug combination method, it is characterized in that, can be made into the double-layer tablet that contains 5～60mg rapid release pioglitazone or its pharmaceutical salts and be no more than 3000mg SRM or its pharmaceutical salts, or can be made into internal layer for being no more than 3000mg SRM or its pharmaceutical salts, outer for containing the pioglitazone of 5～60mg rapid release or the double-layer tablet of its pharmaceutical salts.
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