CN109996545A - For treating the medicinal composition of diabetes B and diabetic keratopathy dyslipidemia - Google Patents

Abstract

The medicinal composition of the diabetes B and dyslipidemia that the present invention relates to a kind of for effectively treating diabetic, more specifically, the present invention provides a kind of medicinal composition, the medicinal composition includes peptidase IV inhibitors gigue column spit of fland or its pharmaceutically acceptable salt and HMG-CoA reductase inhibitor rosuvastatin or its pharmaceutically acceptable salt, effectively to control blood glucose level and improve risk of cardiovascular diseases factor.

Description

For treating the medicinal composition of diabetes B and diabetic keratopathy dyslipidemia

Technical field

The present invention relates to the combination preparations of diabetes B and dyslipidemia for effectively treating diabetic.More Body, the present invention provides a kind of combination preparation, and the combination preparation includes the gigue column spit of fland as inhibitors of dipeptidyl IV Or its pharmaceutically acceptable salt and as the rosuvastatin of HMG-CoA reductase inhibitor or its pharmaceutically acceptable salt Effectively to control blood glucose and improve the risk factors of cardiovascular disease.

Background technique

2011, International Diabetes Federation (IDF) the estimation whole world had 3.66 hundred million people with diabetes.In addition, according to IDF Report, 80% diabetic lives in low income and middle income country, and about 36% diabetic lives in West Pacific region including South Korea.However, it is contemplated that about 1.83 hundred million people are with diabetes but not after diagnosing, IDF estimates full generation Boundary has more than 5.49 hundred million people with diabetes, and it is reported that diabetes caused 4,600,000 people dead in 2011.(international glycosuria Sick federation (International Diabetic Federation), the year two thousand thirty will have 1/10th adult to suffer from glycosuria Sick (One adult in ten will have diabetes by 2030), Press release, Brussels, 2011 year November 14)

Diabetes are a kind of metabolic disorders, wherein due to hypoinsulinism, insulin action deficiency or both and and It is having and cause hyperglycemia.It caused by type 1 diabetes are the destruction because of pancreatic beta cell (beta cell), and is a kind of serious Illness, if without treatment can cause ketosis.In type 1 diabetes patient, it should control blood by insulin therapy Sugar.Type 1 diabetes usually occur in children or young man, it is also possible to it is not fat and showing many years ago for the first time Occur in the adult of hyperglycemic symptoms.The diabetes B increased recently accounts for the 90% to 95% of all diabetes.Diabetes B It is a kind of illness of complexity, and its mechanism is unclear.It usually occurs in adult, but also sees teenager.Its disease Shape is not serious, and shows in a variety of manners.In these symptoms, intricately it is related to dysfunction, the periphery of β cell Insulin resistance, liver glucose metabolic disorder etc..In diabetes B, over time, glycemic control is more tired Difficulty, therefore, in order to suitably control blood glucose, it should the new Hypoylycemic agents of application in average every three or four years.In addition, although with group Therapy and insulinization are closed, but still is difficult to suitably control blood glucose.

American Diabetes Association (ADA) suggest, when type 2 diabetic patient glycated hemoglobin (HbA1c) be 6.5% or When higher, it should start to treat or apply new Hypoylycemic agents.In addition, ADA suggests controlling HbA1c as close possible to non-glycosuria Sick range is reduced at least below 7% as therapeutic purpose, and according to the diabetes stadium or cardiovascular disease of patient (CVD) risk factors classify therapeutic purpose.(diabetes health care standard (Standards of Medical Care in Diabetes).Diabetes Care.2016；39:S1-112)

Diabetes are the major risk factors of cardiovascular disease, while cardiovascular disease is the main of maturity-onset diabetes patient The cause of death.Hypertension and dyslipidemia are also the principal element of cardiovascular disease, to dramatically increase cardiovascular disease Risk.Therefore, in type 2 diabetic patient, it is proposed that should at least assess cardiovascular risk factors (diabetes health care every year Standard (Standards of Medical Care in Diabetes) .Diabetes Care.2016；39:S1-112).

According to UKPDS --- in the larger scale clinical research that Britain carries out, it was reported that in 10 years of diagnosis, Myocardial infarction or apoplexy and angina pectoris occur in about 22% type 2 diabetic patient, and about 30% patient dies of big blood vessel Complication.In this study, the analysis of the risk factors occurred as cardiovascular disease is as a result, LDL-C (low-density lipoprotein gallbladder Sterol) then display highest correlation is sequentially HDL-C (high-density lipoprotein cholesterol), HbA1c, systolic blood pressure and smoking (Turner RC et al., British Medical Journal, volume 1998,316, the 823-828 pages).In this respect, Steno-2 research proves for the first time, can prevent diabetes B in the kinds of risks factor of early stage effectively control cardiovascular disease and suffer from Person occurs the risk of cardiovascular event or reduces the death rate (Gaede P et al., The New England Journal of Medicine, volume 2003,348, the 383-393 pages).This display should actively control other kinds of risks factors and stringent Ground controls blood glucose, to prevent the cardiovascular disease of diabetic.

When using statins, reducing blood cholesterol levels in the kinds of risks factor of cardiovascular disease can be with The fact that reduce the death rate of cardiovascular disease is known.According to using the 4S of Simvastatin (simvastatin) to study, In the case where applying 20mg Simvastatin to the patient with angina pectoris or myocardial infarction, the death rate reduces about 30%.Cause This, statins have been acknowledged as that cardiovascular disease can be reduced by prevention of arterial atherosclerotic plaque rupture Rate and the death rate drug (Pedersen TR et al., Atherosclerosis Supplements, volume 2004,5,81- Page 87).Currently, most of guideline recommendations are using statins as a line medicament of dyslipidemia, wherein using LDL-C as master Want target.

It is known that when LDL-C reduces about 1.0mmol/L, usual serious vascular event, the CVD death rate and the non-lethal heart The risk of flesh infarct reduces 20-25%, and in the risk patient of cardiovascular disease, maintain LDL-C≤1.8mmol/L or with Baseline value shows enough secondary prevention effects compared to reducing by 50%.These results do not have difference in diabetic (Baigent C et al., Lancet, volume 2010,376, the 1670-1681 pages).According to many clinical tests and meta-analysis Result, it was confirmed that therapeutic agent of the statins as dyslipidemia in diabetic, pass through reduce LDL-C concentration And significantly reduce the risk of cardiovascular disease generation.Therefore, statins have been proposed as in diabetic The therapeutic agent of dyslipidemia.In addition, even for the lower patient of cardiovascular risk (such as without cardiovascular disease and 40 years old Patient below), also suggest maintaining the LDL-C of 100mg/dL and the several risk factors for having cardiovascular disease the case where Under, consider application statins come the mode of making the life better (Reiner Z et al., European Heart Journal, 2011, Volume 32, the 1769-1818 pages).

That is, because both the improvement of glycemic control and risk of cardiovascular diseases factor directly affects cardiovascular disease The generation of disease, so for type 2 diabetic patient, it is also very desirable to combination therapy method.

Summary of the invention

Technical problem

Therefore, technical problem of the invention is to provide a kind of combination preparation, and the combination preparation improves type 2 diabetic patient Drug compliance and effectively treatment dyslipidemia and control blood glucose, the dyslipidemia is Diabetes Centre vascular diseases One of major risk factors.

Solution to the problem

In order to solve the above technical problem, the present invention provides a kind of combination preparation, the combination preparation includes to be used as dipeptides The gigue column spit of fland of base peptidase IV inhibitors or its pharmaceutically acceptable salt and the Luo Su as HMG-CoA reductase inhibitor are cut down Statin or its pharmaceutically acceptable salt are as active constituent.

The present invention is described in detail below.

Gigue column spit of fland is that a kind of potent and selective dipeptidyl peptidase-IV (DPP-IV) developed recently relatively inhibits Agent.DPP-IV inhibitor is configured to inhibit the drug of DPP-IV degradation glucagon-like-peptide-1 (GLP-1).GLP-1 is A kind of duodenin in the insulin secretion for promoting β cell, the glucose uptake for increasing peripheral tissues, inhibits α cell Glucose in glucagon secretion and reduction liver works in generating.

Gigue column spit of fland can be used with the various forms of pharmaceutically acceptable salt.In the present invention, the medicine in gigue column spit of fland The example of acceptable salt includes hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, trifluoroacetic acid, formic acid, Malaysia on Acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid and Loprazolam salt, and Tartrate most preferably can be used.

Rosuvastatin is a kind of statins, is 3- hydroxy-3-methyl glutaryl base-coacetylase (HMG-CoA) suppression Preparation.Rosuvastatin has the structure similar with HMG-CoA, therefore rosuvastatin can be inhibited by Reverse transcriptase HMG-CoA reductase treats dyslipidemia to postpone the generation of cholesterol.

Rosuvastatin can be used with the various forms of pharmaceutically acceptable salt.In the present invention, rosuvastatin The example of pharmaceutically acceptable salt include calcium, ammonium, lithium, zinc or magnesium salts, and calcium salt most preferably can be used.

In an embodiment of the invention, combination preparation can be fixed dosage combination, wherein gigue column spit of fland or its Pharmaceutically acceptable salt and rosuvastatin or its pharmaceutically acceptable salt are comprised in single formulation.In the present invention In, it was confirmed that gigue column spit of fland or its pharmaceutically acceptable salt and rosuvastatin or its pharmaceutically acceptable salt are at single dose Do not change its dissolution rate or pharmacokinetic property in type and do not influence each other, to provide fixed dosage combination.

In an embodiment of the invention, fixed dosage combination can also comprising stabilizer, adhesive, disintegrating agent, Lubricant, incremental agent etc. are used as pharmaceutically acceptable excipient.The example of adhesive include but is not limited to polyvinyl acetate, It is vinylpyrrolidone/vinyl acetate copolymer, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone, bright Glue, alginate, cornstarch and potato starch.The example of disintegrating agent include but is not limited to croscarmellose sodium, Crospovidone and sodium starch glycollate.The example of lubricant include but is not limited to colloidal silicon dioxide, aqueous silicon dioxide, Magnesium stearate, sodium stearyl fumarate, Compritol 888 ATO, calcium stearate, stearic acid and talcum.The example of incremental agent includes but not It is limited to microcrystalline cellulose, silicified microcrystalline cellulose, mannitol and lactose.

In an embodiment of the invention, fixed dosage combination may include the two hydration phosphorus to work with stabilizer Sour hydrogen calcium (trade name: DI-TAB, Innophos) is used as pharmaceutically acceptable excipient.Because rosuvastatin is under alkalinity Stablize and unstable under acidity, so regular dosage form is usually using highly basic as excipient.However, gigue column spit of fland is in alkalinity Under it is unstable.It can will be assigned and be stablized to two kinds of active components, that is, gigue column spit of fland and rosuvastatin using calcium phosphate dibasic dihydrate Property.

In an embodiment of the invention, combination preparation can be bilayer tablet, the bilayer tablet include comprising The layer of gigue column spit of fland or its pharmaceutically acceptable salt and layer comprising rosuvastatin or its pharmaceutically acceptable salt.With In the case that the dosage form of bilayer tablet provides combination preparation, dosage form can be more freely prepared without considering gigue column spit of fland and Luo Su Cut down the difference of the physicochemical properties between statin.

In an embodiment of the invention, bilayer tablet can also include stabilizer, adhesive, disintegrating agent, lubrication Agent, incremental agent etc. are used as pharmaceutically acceptable excipient.The example of adhesive includes but is not limited to polyvinyl acetate, ethylene Base pyrrolidone/vinyl acetate copolymer, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone, gelatin, sea Alginates, cornstarch and potato starch.The example of disintegrating agent includes but is not limited to croscarmellose sodium, is crosslinked and gathers Tie up ketone and sodium starch glycollate.The example of lubricant includes but is not limited to colloidal silicon dioxide, aqueous silicon dioxide, stearic acid Magnesium, sodium stearyl fumarate, Compritol 888 ATO, calcium stearate, stearic acid and talcum.The example of incremental agent is including but not limited to micro- Crystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose and a Lactose hydrate.

In an embodiment of the invention, the layer comprising gigue column spit of fland of bilayer tablet can preferably comprise stearic richness Horse acid sodium is as lubricant.And if other comprising sodium stearyl fumarate as lubricant in the layer comprising gigue column spit of fland Lubricant is compared, which can assign higher stability to gigue column spit of fland.

In an embodiment of the invention, the layer comprising rosuvastatin of bilayer tablet may include with stabilizer The calcium phosphate dibasic dihydrate (trade name: DI-TAB, Innophos) to work is used as pharmaceutically acceptable excipient.If packet Containing calcium phosphate dibasic dihydrate as excipient, then the generation of impurity can be prevented by helping the stabilisation of rosuvastatin.

In an embodiment of the invention, combination preparation can preferably comprise 25 to the gigue column spit of fland 100mg or pharmacy Upper acceptable salt, and more preferable 40 to the gigue column spit of fland 80mg or pharmaceutically acceptable salt.

In an embodiment of the invention, combination preparation can preferably comprise 1 to 50mg rosuvastatin or its medicine Acceptable salt on, and more preferable 3 to 40mg rosuvastatin or its pharmaceutically acceptable salt.

In an embodiment of the invention, combination preparation may include such as 50mg gigue column spit of fland or can pharmaceutically connect The salt and 5mg rosuvastatin received or its pharmaceutically acceptable salt, the gigue column spit of fland 50mg or pharmaceutically acceptable salt and 10mg rosuvastatin or its pharmaceutically acceptable salt, the gigue column spit of fland 50mg or pharmaceutically acceptable salt and 20mg Luo Su are cut down Statin or its pharmaceutically acceptable salt or the gigue column spit of fland 50mg or pharmaceutically acceptable salt and 40mg rosuvastatin or Its pharmaceutically acceptable salt.

In an embodiment of the invention, combination preparation can be film coating.Available reagent in film coating layer It may include conventional reagent, such as, but not limited to hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone,Series,Series.

Effect of the invention

According to the present invention, providing a kind of includes gigue column spit of fland or pharmaceutically acceptable salt and rosuvastatin or its medicine The combination preparation of acceptable salt on, the combination preparation can improve the drug compliance of patient, effectively treatment diabetes The dyslipidemia of patient and diabetes B is effectively treated by glycemic control.

Detailed description of the invention

Fig. 1 is the figure of the variation of Hb1Ac when indicating to visit every time (%).

Fig. 2 is the figure of the variation of LDL-C when indicating to visit every time (mg/dL).

Specific embodiment

Hereinafter, the present invention is explained in greater detail by following embodiment.It must be understood, however, that guarantor of the invention Shield range is not limited to the embodiment.

Embodiment 1: the preparation of fixed dosage

The fixed dosage combination for being prepared for 3 kinds of preparations, in 3 kinds of preparations, rosuvastatin are constituted according to the component of table 1 The content in spit of fland is different.

[table 1]

1) Supertab 21AN: Lactis Anhydrous

2) Prosolv SMCC 50: silicified microcrystalline cellulose

3) DI-TAB: calcium phosphate dibasic dihydrate

4) Kollidon VA64: vinylpyrrolidone/vinyl acetate copolymer

Embodiment 2: the preparation of bilayer tablet

The bilayer tablet for being prepared for 3 kinds of preparations, in 3 kinds of preparations, rosuvastatin are constituted according to the component of table 2 Content is different.Preparation method in table 3 as presented.

[table 2]

1) 100: one Lactose hydrate of Flowlac

2) DI-TAB: calcium phosphate dibasic dihydrate

3) Kollidon VA63: vinylpyrrolidone/vinyl acetate copolymer

[table 3]

Embodiment 3: stability test

The stability examination of the bilayer tablet preparation prepared in embodiment 2 is carried out under acceleration environment (40 DEG C, 75% humidity) It tests 6 months.As a result as presented in table 4.

[table 4]

DP-IMP-1:

2- [fluoro- 2,3,5,6,7,8- hexahydro imidazo [1,2-a] pyridine -2- base of (2S) -6,6- two] -1- [2,4- bis- (three Methyl fluoride) -5,6,7,8- tetrahydropyridine simultaneously [3,4-d] pyrimidin-7-yl] -1- ethyl ketone

DP-IMP-2:

(the trifluoromethyl) -5,6,7,8- of 2,4- bis- tetrahydropyridine simultaneously [3,4-d] pyrimidin-8-ones

DP-IMP-3:

(3S) -3- amino -4- (the fluoro- 2- oxo-piperidine base of 5,5- bis-) -1- [two (trifluoromethyl) -5,6 8- hydroxyl -2,4-, 7,8- tetrahydropyridine simultaneously [3,4-d] pyrimidin-7-yl] butyl- 1- ketone tartrate

5- oxo:

Bis- (6E) -7- [4- (4- fluorophenyl) -6- isopropyl -2- [methyl (methyl sulphonyl) amino] pyrimidine -5- base] (3R) -3- hydroxyl -5- oxo hept- 6- olefin(e) acid

Lactone:

N- (4- (4- fluorophenyl) -5- (1E) -2- [(2S, 4R) -4- hydroxyl -6- oxo tetrahydro -2H- pyrans -2- base] ethylene Base] -6- isopropylpyrimidin -2- base }-N- methylmethane sulfonamide

GS-IMP-1:

1- [(S) -2- [(3R, 5R, E) -7- { 2- [N- methyl (methyl sulphonyl) amino] -4- (p-fluorophenyl) -6- isopropyl Base -5- pyrimidine radicals } -3,5- dihydroxy -6- heptene acylamino-] -4- [bis- three azepine -5,6,7 (trifluoromethyl) -1,3,7- 2,4-, 8- naphthane -7- base] -4- oxo butyl] two fluoro- 2- piperidones of -5,5-

From table 4, it can be seen that being known that all formulations all met impurity receives standard from the result of stability test.

Embodiment 4: clinical research

In order to evaluate gigue column spit of fland/rosuvastatin fixed dosage combination (FDC) in the 2 type glycosurias with dyslipidemia Effect and safety in patient, according to the guide of composition of medicine clinical research, by described effect and safety and every kind of list One therapy is compared.

According to the clinical research guide that Korean foods and drug safety portion issue, usually in the III phase of Remedies for diabetes In clinical test, drug should apply 24 weeks or the longer time, and in the III clinical trial phase of dyslipidemia therapeutic agent, medicine Object should apply 12 weeks or the longer time.Therefore, effect, 24 weeks quilts are evaluated after medicament administration 24 weeks for clinical test Think to be sufficient to the effect of proving gigue column spit of fland and rosuvastatin.

The melbine for being designed to background therapy is a kind of Hypoylycemic agents of oral administration, is widely used as 2 types The line monotherapy of diabetic.As the Hypoylycemic agents of other oral administrations, since melbine is difficult to be connected Continuous glycemic control, it is therefore desirable to be combined with the novel blood sugar lowing agent of oral administration, the novel blood sugar lowing agent of the oral administration It is effective and there is good drug tolerance.Because confirmed in III clinical trial phase gigue column spit of fland with diformazan Effect when biguanides combines to blood glucose is reduced, so gigue column spit of fland can be used in combination treatment together with melbine.Therefore, In the clinical research, the unresponsive patient of melbine will be included in study population.

Furthermore, it is contemplated that the dose dependent adverse events for the rosuvastatin recognized by the result of various researchs and The increased systemic exposure (the intermediate value increase about two (2) of AUC and Cmax times) in Asian, by the dosage of rosuvastatin with 8 The interval in week increases to maximum dose (20mg) from predose pressure, and every 8 weeks evaluation effects and safety.

For the type 2 diabetic patient with dyslipidemia, represented in patient itself or patient by agreeing in writing to submit In the case of, screening test is carried out to determine patient if appropriate for/exclusion criteria is included in, wherein the patient is to fixed dosage diformazan Biguanides (>=1,000 mg/day) monotherapy is reactionless.Make to be suitble to be included in/subject of exclusion criteria is subjected to TLC (treatment life Order cyclomorphosis) phase is for 2 weeks, and then pass through single blind study during 2 weeks introduction period (run-in period) and always co-administers 3 Piece placebo (placebo (gigue column spit of fland/rosuvastatin FDC), placebo (gigue column spit of fland) and placebo (rosuvastatin Spit of fland)).Before the 1st time is visited in 4 weeks in the case where application dyslipidemia therapeutic agent, in 4 weeks elution phases (wash-out Period after), 2 weeks TLC phases and 2 week introduction period are carried out.

Then following subject is assigned randomly in a group in 3 groups, wherein visiting (randomization at the 3rd time；The 0 week) when, background therapy (melbine, >=1,000 mg/day) and the 3 tablets of placebos in total applied during 2 week introduction period (are pacified Console agent (gigue column spit of fland/rosuvastatin FDC), placebo (gigue column spit of fland) and placebo (rosuvastatin)) every kind of drug Compliance is 70% or higher, and the test result obtained when visiting for the 2nd time meets and is included in/exclusion criteria.

Then during 24 weeks in total application phases, subject visited at the 8th week, the 16th week and the 24th week, and including Total clinical research phase of elution phase, TLC phase and introduction period are about 28-32 weeks.

(randomization is visited according to the 3rd time；0th week) it arranges to visit, then the 4th visits (the 8th week), the 5th visits (the 16 weeks) and visit for the 6th time (the 24th week) visit the permission phase be ± 10 days.

During including all clinical research phases of elution phase, TLC phase and introduction period, subject deactivates to remove and grind for clinic Possibility except the drug studied carefully influences the dyslipidemia therapeutic agent (including complementarity health food) of lipid value, maintains background therapy (melbine, >=1,000 mg/day), and allow with conventional movement/diet control, but do not significantly change life mould Formula.

Embodiment 4-1: the treatment of application

After randomization, every morning gives 3 in total (each 1) as shown in table 5 in Conventional Time once a day, holds Continuous 24 weeks in total.However, in some cases, subject can face visit before wanting seeking time to take.

[table 5]

Background therapy: according to specified dosage, daily Conventional Time apply melbine (>=1000 milligrams/ It).

For all subjects, regardless of LDL-C level, all forced to increase rosuvastatin according to following methods.So And if subject cannot force to increase dosage due to safety issue, reason is suitably described in case report and is adjusted The dosage of whole rosuvastatin.

(the 0th week) to the 4th is visited from the 3rd time and visits (the 8th week) application rosuvastatin 5mg once a day, continues 8 Week.

(the 8th week) to the 5th is visited from the 4th and visits (the 16th week) application rosuvastatin 10mg once a day, is continued 8 weeks.

(the 16th week) is visited from the 5th and applies rosuvastatin 20mg once a day to (the 24th week) is visited for the 6th time, is held It is 8 weeks continuous.

Embodiment 4-2: the method that subject is assigned to treatment group

In the clinical research, randomized table is formulated by layering district's groups randomization by double-blind trial.It is random to carry out Change, statistician is considering that (HbA1c is more than or less than when visiting for the 2nd time for predefined district's groups size and stratification factor 8.5%) under by using9.2 editions are distributed the randomization numerical value of enough size.By interactive network response system (IWRS) it is used for the randomization of the clinical research.Tester is passed through defeated by given ID and the website cryptographic acess IWRS The information for entering subject required for being randomized is randomized according to the sequence that subject registers.Distribute kit number and Randomization Number should also announce randomization code to maintain double blind when urgent by IWRS.During the clinical research, Randomization code is not announced.

Embodiment 4-3: blind

The clinical research is that double-blind trial, wherein tester and subject do not know that the drug for clinical research is to survey Reagent object or placebo are to maintain the objectivity of test result.However, because only applying placebo during the introduction period, Single blind trial is carried out in the period.

In order to maintain double blind, in the experimental study, using in appearance cannot with testing drug distinguish in identical system Placebo in agent, and them are distinguished for being randomly assigned with kit number.Therefore, randomization code is only formulated Responsible person, code Librarian and IWRS administrator know which group subject is assigned to, and including tester and subject Other research participants do not know.

By in all test result input databases and after locking DB, LG Chemical Ltd (LG Chem.Ltd.) The responsible person of (pervious LG life science Co., Ltd (LG Life Sciences Ltd.)) is known that randomized results.

Embodiment 4-4: the compliance for the treatment of is studied

In order to evaluate compliance, it will thus provide taken to the testing drug/composition of medicine, the drug given back and subject of subject The amount of drug is recorded in case notes.Drug compliance is calculated according to the following formula.

* the calculating of every kind of drug dose

[gigue column spit of fland/rosuvastatin FDC and gigue column spit of fland 50mg]

Visit that (the 0th week)~the 4th visits (the 8th week), the 4th visits (the 8th week)~the 5th and visits the (the 16th for-the 3 time Week), the 5th visits (the 16th week)~the 6th time and visits (the 24th week): 56 (once a day, continuing 8 weeks)

[rosuvastatin]

Visit (the 0th week)~the 4th and visit (the 8th week) for-the 3 time: (1 (5mg) continues 8 once a day within 5mg*56 days All (dose * number of days))

The 4th is visited (the 8th week)~the 5th and visited (the 16th week): (1 (X mg), once a day, hold X mg*56 days It is 8 weeks (dose * number of days) continuous)

The 5th is visited (the 16th week)~the 6th time and visited (the 24th week): (1 (X mg), once a day, hold X mg*56 days It is 8 weeks (dose * number of days) continuous)

It is in the past once conventional to visit during visiting~the 6 time at the 3rd time and visiting when specified reduction rosuvastatin The dosage for starting the previous day is reduced in terms of X mg, and since the day reducing visit the previous day to next routine with reduced agent Meter.

- X mg: the daily dosage for the rosuvastatin that subject takes during the 4th is visited~the 6 time and visited

In the case where dropping by the wayside, the compliance for visiting the phase is visited the amount that should be taken according to preceding primary routine and is calculated, and It is included in total compliance.

Embodiment 4-5: efficacy assessments

Parameter for efficacy assessments is defined as follows:

● glycated hemoglobin (HbA1c)

The reduction of known HbA1c is related with the risk reduction of microvascular complication occurs.HbA1c is commonly used for 1 type of measurement With the optimal primary efficacy evaluation parameter of glycemic control state long-term in diabetes B, and reflect 2-3 months in the past Average blood glucose levels.The blood collected by using the analysis of the HbA1c measuring method of standardization and verifying.

● low density lipoprotein cholesterol (LDL-C)

LDL-C level is the primary evaluation item of norcholesterol therapy.Lipoid dyscrasias refers mainly to hypercholesterolemia, and special Not, there are many Epidemiological Evidence show serum LDL-C it is horizontal between the risk of coronary artery disease there are correlation and Causality.In addition, other clinical symptoms of atherosclerosis are horizontal related to blood LDL-C.That is, because working as The risk of coronary artery disease reduces when LDL-C is reduced, so LDL-C is set to prevention cardiovascular disease and dead substitution Index, wherein prevention cardiovascular disease and death are to treat the main target of lipoid dyscrasias.

● fasting plasma glucose (FPG)

As efficacy assessments parameter, has checked the fasting plasma glucose after applying the drug for clinical research and control Variation.

● Diagnostic Value of Fasting Serum insulin

In the case where reducing blood insulin amount according to the use of oral hypoglycemic agents, it may be considered that insulin resistance Improve and consider the reduction of HbA1c level.Therefore, the drug which is designed to evaluation for clinical research is to this respect Effect.

● Diagnostic Value of Fasting Serum proinsulin

In diabetes B, due to the dysfunction of β cell, insulin is not processed completely, and proinsulin is dense Degree increases.The parameter is designed to be used for the drug of clinical research to β cell by fasting insulin original/insulin ratio evaluation The effect of function.

● Diagnostic Value of Fasting Serum C- peptide

C- peptide is the counterpart separated when processing insulin from precursor proinsulin.Because C- peptide and insulin are with 1:1 Ratio exist, so it is possible thereby to indirectly confirm pancreatic beta cell insulin secreting ability.Therefore, which is designed Effect of the drug of clinical research to this respect is used at evaluation.

● HOMA- β (Homeostasis model assessment)

The parameter be designed to evaluation by the drug of clinical research to the effect of β cell function and according to the following formula based on It calculates.

● HOMA-IR (HOMA- insulin resistance)

The parameter is designed to effect of the evaluation for the drug of clinical research to insulin resistance.

● weight and waistline

Because obesity will increase insulin resistance and cardiovascular disease, these parameters are designed to evaluation for clinic The effect of the drug of research in this respect.

● empty stomach lipid parameter (total cholesterol, HDL-C, triglycerides)

Since total cholesterol (TC), triglycerides (TG) and HDL-C are increasingly being used as the son ginseng of dyslipidemia treatment Number, therefore should be evaluated them as secondary evaluation parameter.Hypertriglyceridemia be cardiovascular disease another solely Vertical risk factors, and be the risk factors of pancreatitis.In contrast, the low blood level of HDL-C is the wind of cardiovascular disease Dangerous factor, particularly, in type 2 diabetic patient, the low blood level of HDL-C generally entails hypertriglyceridemia, and It is considered as important factor as LDL-C.

● empty stomach LDL-C/HDL-C ratio

The blood lipoprotein distribution characteristics for causing artery sclerosis is that high LDL-C, low HDL-C and adjoint TG increase.With list Only LDL-C is compared, and LDL-C/HDL-C ratio is the more effective predictable factor of risk of cardiovascular diseases.It is reported that if A possibility that ratio > 5 LDL-C/HDL-C are higher, then coronary artery disease is undergone in 8 years is 19.2%, and if companion It is higher that the then possibility is increased with TG.The parameter is designed to evaluation and is used for the effect of the drug of clinical research in this respect.

● Diagnostic Value of Fasting Serum Apo A-I, Diagnostic Value of Fasting Serum Apo B, Diagnostic Value of Fasting Serum Apo B/Apo A-I ratio

Apo A-1 be constitute the major apolipoprotein of HDL-C and be considered as cardiovascular risk as HDL-C because Element.Apo B is the major apolipoprotein for constituting LDL-C, and is existed with LDL-C with 1:1 ratio.Apo B is evaluated with LDL-C It equally uses, and known high TG level is more accurate than LDL-C in terms of evaluation of estimate.Therefore, Apo B/Apo A-I ratio is One of predictive factors of risk of cardiovascular diseases.

● Diagnostic Value of Fasting Serum Lp (a)

Lipoprotein (a) is a kind of low-density lipoprotein connecting with apolipoprotein (a).High Lp (a) level and coronary artery Disease and the increase of the risk of ishemic stroke are related, especially in cardiovascular disease high risk person, it is proposed that carry out Lp (a) and comment Valence.

(1) primary efficacy evaluation result

The primary efficacy evaluation parameter of the clinical research be when visiting (the 24th week) the 6th time HbA1c and LDL-C relative to Visit (randomization for 3 times；0th week) baseline variation.Variable quantity and change rate (%) are respectively used to HbA1c and LDL-C.

For HbA1c, gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group variable quantity is compared.For LDL-C compares the change rate of gigue column spit of fland/rosuvastatin FDC group and gigue column spit of fland group.Compared by each, it was confirmed that Gigue column spit of fland/rosuvastatin FDC group superiority.

<HbA1c>

Every group of HbA1c baseline is respectively as follows: 7.79 ± 0.79%, He Luosu of gigue column spit of fland/rosuvastatin FDC group and cuts down The 7.78 ± 0.78% of statin group, and (P=0.9537) is not significantly different between group.

HbA1c baseline is presented as the analysis of covariance (ANCOVA) result such as table 6 of covariant.

When visiting (the 24th week) at the 6th time, compared with baseline, the LS average value (least square average value) of HbA1c variation Are as follows: the 0.273 ± 0.080% of gigue column spit of fland/rosuvastatin FDC group -0.539 ± 0.081% and rosuvastatin group. Gigue column spit of fland/rosuvastatin FDC group shows the significant decrease (P < 0.0001) compared with baseline, and on the contrary, rosuvastatin Group display dramatically increases (P=0.0007) compared with baseline.

The difference of variable quantity between two groups is -0.812 ± 0.113%, and in gigue column spit of fland/rosuvastatin In FDC group, compared with rosuvastatin group, HbA1c is substantially reduced.95%CI (- 1.035, -0.588) from the upper limit less than 0, Confirm superiority (P < 0.0001) of the gigue column spit of fland/rosuvastatin FDC group in terms of the effect of reducing HbA1c.

[table 6]

<LDL-C>

Every group of LDL-C baseline is respectively as follows: 133.39 ± 25.84mg/dL of gigue column spit of fland/rosuvastatin FDC group, and 141.99 ± 29.58mg/dL of gigue column spit of fland group, and (P=0.0263) is not significantly different between group.

LDL-C baseline is presented as the analysis of covariance (ANCOVA) result such as table 7 of covariant.

When visiting (the 24th week) at the 6th time, compared with baseline, (least square is flat for the LS average value of LDL-C change rate (%) Mean value) are as follows:-the 1.135 of gigue column spit of fland/rosuvastatin FDC group -53.002 ± 1.929% and gigue column spit of fland group ± 1.939%.Gigue column spit of fland/rosuvastatin FDC group, which is shown, significantly reduces (P < 0.0001) compared with baseline, and gigue column spit of fland group It is displayed without significant changes (P=0.5587).

The difference of change rate between two groups is -51.867 ± 2.745%, and in gigue column spit of fland/rosuvastatin In FDC group, compared with the group of gigue column spit of fland, LDL-C is substantially reduced.95%CI (- 57.271, -46.463) from the upper limit less than 0, Confirm superiority (P < 0.0001) of the gigue column spit of fland/rosuvastatin FDC group in terms of the effect of reducing LDL-C.

[table 7]

(2) secondary efficacy evaluation result

As secondary efficacy evaluation parameter, the HbA1c and LDL-C compared with baseline is had rated the 6th time when visiting (the 24th week) Variation.For HbA1c, the variable quantity of gigue column spit of fland/rosuvastatin FDC group and gigue column spit of fland group is compared.For LDL- C compares gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group change rate.

<HbA1c>

Every group of HbA1c baseline is respectively as follows: gigue column spit of fland/rosuvastatin FDC group 7.79 ± 0.79% and gigue column The 7.79 ± 0.78% of spit of fland group, and (P=0.8923) is not significantly different between group.

LDL-C baseline is presented as the analysis of covariance (ANCOVA) result such as table 8 of covariant.

When visiting (the 24th week) at the 6th time, compared with baseline, (least square is average for the LS average value of HbA1c variable quantity Value) are as follows:-the 1.007 of gigue column spit of fland/rosuvastatin FDC group -0.539 ± 0.081% and gigue column spit of fland group ± 0.081%.Two groups all show compared with baseline significant decrease (P < 0.0001), but gigue column spit of fland/rosuvastatin FDC group and Gigue column spit of fland group, which is compared, shows that smaller HbA1c is reduced, and there are statistically-significant difference (P=0.0001).

[table 8]

<LDL-C>

Every group of LDL-C baseline is respectively as follows: 133.39 ± 25.84mg/dL of gigue column spit of fland/rosuvastatin FDC group, and 133.63 ± 27.20mg/dL of rosuvastatin group, and (P=0.9747) is not significantly different between group.

LDL-C baseline is presented as the analysis of covariance (ANCOVA) result such as table 9 of covariant.

When visiting (the 24th week) at the 6th time, compared with baseline, (least square is flat for the LS average value of LDL-C change rate (%) Mean value) are as follows:-the 54.288 of gigue column spit of fland/rosuvastatin FDC group -53.002 ± 1.929% and rosuvastatin group ± 1.909%.Two groups all show the significant decrease (P < 0.0001) compared with baseline, and the LDL-C change rate of two groups does not have Significant difference (P=0.6354).

[table 9]

(3) other efficacy assessments results

<variation of HbAlc (%) when visiting every time>

Variation such as Fig. 1 of the Hb1Ac (%) of subject is presented during entire clinical research.

Every group of HbA1c baseline are as follows: gigue column spit of fland/rosuvastatin FDC group 7.79 ± 0.79%, gigue column spit of fland group 7.79 ± 0.78% and rosuvastatin group 7.78 ± 0.78%, and (P=0.9900) is not significantly different between group. In gigue column spit of fland/rosuvastatin FDC group and gigue column spit of fland group, when visiting every time of (the 24th week) is being visited until the 6th time HbA1c significantly reduces (P < 0.0001) compared with baseline, but in rosuvastatin group, HbA1c does not have significant changes, and phase Instead, (0.27 ± 0.83%, P=0.0016) is dramatically increased when visiting (the 24th week) at the 6th time.

HbA1c baseline is presented as the analysis of covariance (ANCOVA) result such as table 10 of covariant.

LS average value (the least square of HbA1c when visiting more every time between described group relative to the variation of baseline Average value) when, gigue column spit of fland/rosuvastatin FDC group shows that HbA1c is significant compared with rosuvastatin group in all visit It reduces, but shows with the group of gigue column spit of fland compared with and smaller to reduce that (reduction that the 5th visits (the 16th week) HbA1c later is significant It is smaller).

[table 10]

<variation of LDL-C (%) when visiting every time>

The variation of the LDL-C of subject such as Fig. 2 is presented during entire clinical research.

Every group of LDL-C baseline are as follows: 133.39 ± 25.84mg/dL of gigue column spit of fland/rosuvastatin FDC group, gigue column 141.99 ± 29.58mg/dL of spit of fland group and 133.63 ± 27.20mg/dL of rosuvastatin group, and there are statistics to show It writes difference (P=0.0267).In gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group, visited until the 6th time The LDL-C significant decrease (P < 0.0001) with baseline compared with when visiting every time of (the 24th week), and in the group of gigue column spit of fland, the LDL-C significantly reduces (P < 0.05) compared with baseline when visiting (the 8th week) and visit (the 24th week) for the 6th time for 4 times.

LDL-C baseline is presented as the analysis of covariance (ANCOVA) result such as table 11 of covariant.

LS average value (the least square of LDL-C when visiting more every time between described group relative to the variation of baseline Average value) when, gigue column spit of fland/rosuvastatin FDC group shows that LDL-C significantly drops compared with the group of gigue column spit of fland in all visit It is low, and significant difference is displayed without compared with rosuvastatin group in all visit.

[table 11]

<variation of fasting plasma glucose (mg/dL) when visiting every time>

FPG baseline is presented as the analysis of covariance (ANCOVA) result such as table 12 of covariant.

(least square is flat relative to the LS average value of the variation of baseline by FPG when visiting more every time between described group Mean value) when, gigue column spit of fland/rosuvastatin FDC group shows significant smaller FPG in all visit compared with the group of gigue column spit of fland It reduces, but shows that significant bigger FPG is reduced compared with rosuvastatin group in all visit.

[table 12]

<variation of total cholesterol (mg/dL) when visiting every time>

TC when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline LS average value (most Small two multiply average value) when, gigue column spit of fland/rosuvastatin FDC group shows that significant bigger TC is reduced compared with the group of gigue column spit of fland, And show that TC variation is not significantly different (table 13) compared with rosuvastatin group.

[table 13]

<variation of HDL-C (mg/dL) when visiting every time>

The LS average value of HDL-C when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), gigue column spit of fland/rosuvastatin FDC group shows that HDL-C variation does not have compared with the group of gigue column spit of fland Significant difference, and show that significant smaller HDL-C increases (table 14) compared with rosuvastatin group.

[table 14]

<when visiting every time triglycerides (TG, mg/dL) variation>

TG when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline LS average value (most Small two multiply average value) when, gigue column spit of fland/rosuvastatin FDC group shows that TG is significantly reduced compared with the group of gigue column spit of fland, and shows Show that TG variation is not significantly different (table 15) compared with rosuvastatin group.

[table 15]

<variation of LDL-C/HDL-C ratio when visiting every time>

Variation of the LDL-C/HDL-C ratio relative to baseline when comparing the 6th time and visiting (the 24th week) between described group LS average value (least square average value) when, gigue column spit of fland/rosuvastatin FDC group shows compared with the group of gigue column spit of fland significant Bigger LDL-C/HDL-C ratio reduces, and shows that LDL-C/HDL-C ratio does not have significance difference compared with rosuvastatin group Different (table 16).

[table 16]

<variation of weight (kg) when visiting every time>

The LS average value of weight when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), gigue column spit of fland/rosuvastatin FDC group shows the significant smaller body compared with rosuvastatin group It reduces again, and shows that weight is not significantly different (table 17) compared with the group of gigue column spit of fland.

[table 17]

<variation of waistline (cm) when visiting every time>

The LS average value of waistline when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), gigue column spit of fland/rosuvastatin FDC group shows that waistline is not shown compared with other two control groups It writes difference (table 18).

[table 18]

<variation of empty stomach serum insulin (uIU/mL) at the 24th week>

The variation such as table 19 of the Diagnostic Value of Fasting Serum insulin of subject is in compared with baseline when visiting (the 24th week) at the 6th time It is existing.

Every group of Diagnostic Value of Fasting Serum insulin baseline is similar: 9.26 ± 4.42uIU/ of gigue column spit of fland/rosuvastatin FDC group ML, 11.02 ± 10.59uIU/mL of gigue column spit of fland group and 9.12 ± 3.95uIU/mL of rosuvastatin group.It is visited at the 6th time When visiting (the 24th week), gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group show the Diagnostic Value of Fasting Serum pancreas islet compared with baseline Element dramatically increases, and gigue column spit of fland group shows and is not significantly different compared with baseline.

The variation of Diagnostic Value of Fasting Serum insulin when comparing the 6th time and visiting (the 24th week) between described group relative to baseline When LS average value (least square average value), wherein the LS average value is by Diagnostic Value of Fasting Serum insulin baseline as covariant The analysis of covariance (ANCOVA) obtains, and gigue column spit of fland/rosuvastatin FDC group shows the Diagnostic Value of Fasting Serum pancreas compared with the group of gigue column spit of fland Island element increases, and Diagnostic Value of Fasting Serum insulin reduces compared with rosuvastatin group.However, being neither dramatically different.

[table 19]

<variation of empty stomach serum proinsulin (uIU/mL) at the 24th week>

When visiting (the 24th week) at the 6th time compared with baseline the variation of the Diagnostic Value of Fasting Serum proinsulin of subject such as 20 institute of table It presents.

Every group of Diagnostic Value of Fasting Serum proinsulin baseline is similar: gigue column spit of fland/rosuvastatin FDC group 14.99 ± 11.11uIU/mL, 17.64 ± 15.77uIU/mL of gigue column spit of fland group and 14.77 ± 10.52uIU/ of rosuvastatin group mL.When visiting (the 24th week) at the 6th time, gigue column spit of fland/rosuvastatin FDC group shows no significant changes compared with baseline, Gigue column spit of fland group shows that Diagnostic Value of Fasting Serum proinsulin significantly reduces compared with baseline, and rosuvastatin group is shown and baseline phase It is dramatically increased than Diagnostic Value of Fasting Serum proinsulin.

Variation of the Diagnostic Value of Fasting Serum proinsulin relative to baseline when comparing the 6th time and visiting (the 24th week) between described group LS average value (least square average value) when, wherein the LS average value by Diagnostic Value of Fasting Serum proinsulin baseline as covariant The analysis of covariance (ANCOVA) of amount obtains, and gigue column spit of fland/rosuvastatin FDC group shows the fasting blood compared with the group of gigue column spit of fland Clear proinsulin dramatically increases, and variable quantity is not significantly different compared with rosuvastatin group.

[table 20]

<variation of empty stomach Serum C-peplide (ng/mL) at the 24th week>

The variation such as table 21 of the Diagnostic Value of Fasting Serum C- peptide of subject is in compared with baseline when visiting (the 24th week) at the 6th time It is existing.

Every group of Diagnostic Value of Fasting Serum C- peptide baseline is similar: 2.14 ± 0.89ng/mL of gigue column spit of fland/rosuvastatin FDC group, 2.48 ± 1.29ng/mL of gigue column spit of fland group and 2.23 ± 0.86ng/mL of rosuvastatin group.The (the 24th is visited at the 6th time Week) when, all 3 groups all show no significant changes compared with baseline.

The LS of Diagnostic Value of Fasting Serum C- peptide when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When average value (least square average value), wherein the LS average value passes through association side of the Diagnostic Value of Fasting Serum C- peptide baseline as covariant Difference is analysed (ANCOVA) and is obtained, and gigue column spit of fland/rosuvastatin FDC group shows that Diagnostic Value of Fasting Serum C- peptide is aobvious compared with the group of gigue column spit of fland It writes and increases, and variable quantity is not significantly different compared with rosuvastatin group.

[table 21]

<empty stomach serum proinsulin/insulin ratio variation at the 24th week>

When visiting (the 24th week) at the 6th time compared with baseline subject Diagnostic Value of Fasting Serum proinsulin/insulin ratio Variation such as table 22 is presented.

Every group of Diagnostic Value of Fasting Serum proinsulin/insulin ratio baseline is similar: gigue column spit of fland/rosuvastatin FDC group 0.23 ± 0.13, the 0.23 ± 0.13 of 0.24 ± 0.13 and rosuvastatin group of gigue column spit of fland group.The (the 24th is visited at the 6th time Week) when, gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group show no significant changes compared with baseline, and lucky Ge Lieting group shows that Diagnostic Value of Fasting Serum proinsulin/insulin ratio significantly reduces compared with baseline.

Diagnostic Value of Fasting Serum proinsulin/insulin ratio when comparing the 6th time and visiting (the 24th week) between described group is opposite When LS average value (the least square average value) of the variation of baseline, wherein the LS average value passes through Diagnostic Value of Fasting Serum insulin Original/insulin ratio baseline is obtained as the analysis of covariance (ANCOVA) of covariant, gigue column spit of fland/rosuvastatin FDC group Display Diagnostic Value of Fasting Serum proinsulin/insulin ratio compared with the group of gigue column spit of fland increases, but not dramatically different, and shows Variable quantity is not significantly different compared with rosuvastatin group.

[table 22]

<variation of HOMA- β at the 24th week>

The variation such as table 23 of the HOMA- β of subject is presented compared with baseline when visiting (the 24th week) at the 6th time.

Every group of HOMA- β baseline is similar: gigue column spit of fland/rosuvastatin FDC group 46.86 ± 27.22, gigue column spit of fland The 42.76 ± 25.74 of 50.76 ± 37.16 and rosuvastatin group of group.When visiting (the 24th week) at the 6th time, gigue column spit of fland/ Rosuvastatin FDC group and gigue column spit of fland group show that HOMA- β is dramatically increased compared with baseline, but rosuvastatin group show with Baseline does not have significant changes compared to HOMA- β.

The LS average value of HOMA- β when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), wherein the LS average value passes through the analysis of covariance of the HOMA- β baseline as covariant (ANCOVA) it obtaining, gigue column spit of fland/rosuvastatin FDC group shows that HOMA- β is dramatically increased compared with rosuvastatin group, and And variable quantity is not significantly different compared with the group of gigue column spit of fland.

[table 23]

<variation of HOMA-IR at the 24th week>

The variation such as table 24 of the HOMA-IR of subject is presented compared with baseline when visiting (the 24th week) at the 6th time.

Every group of HOMA-IR baseline is similar: gigue column spit of fland/rosuvastatin FDC group 3.23 ± 1.67, gigue column spit of fland group 4.10 ± 4.65 and rosuvastatin group 3.37 ± 1.63.When visiting (the 24th week) at the 6th time, gigue column spit of fland/Luo Su is cut down Statin FDC group and gigue column spit of fland group show that compared with baseline, HOMA-IR does not have a significant changes, and rosuvastatin group show with Baseline is dramatically increased compared to HOMA-IR.

HOMA-IR when comparing the 6th time and visiting (the 24th week) between described group is average relative to the LS of the variation of baseline When being worth (least square average value), wherein the LS average value passes through the analysis of covariance of the HOMA-IR baseline as covariant (ANCOVA) it obtaining, gigue column spit of fland/rosuvastatin FDC group shows that HOMA- β is significantly reduced compared with rosuvastatin group, and And variable quantity is not significantly different compared with the group of gigue column spit of fland.

[table 24]

<variation of serum Apo A-I (mg/mL) at the 24th week>

The variation such as table 25 of the Apo A-I of subject is presented compared with baseline when visiting (the 24th week) at the 6th time.

Every group of Apo A-I baseline is similar: 145.24 ± 24.51mg/dL of gigue column spit of fland/rosuvastatin FDC group, lucky 144.47 ± 22.37mg/dL of Ge Lieting group and 142.14 ± 24.75mg/dL of rosuvastatin group.It is visited at the 6th time When (the 24th week), gigue column spit of fland/rosuvastatin FDC group and gigue column spit of fland group show that Apo A-I is not significant compared with baseline Variation, and rosuvastatin group shows that Apo A-I is dramatically increased compared with baseline.

Apo A-I when comparing the 6th time and visiting (the 24th week) between described group is average relative to the LS of the variation of baseline When being worth (least square average value), wherein the LS average value passes through the analysis of covariance of the Apo A-I baseline as covariant (ANCOVA) it obtains, gigue column spit of fland/rosuvastatin FDC group shows that variable quantity is not significantly different compared with two control groups.

[table 25]

<variation of serum Apo B (mg/dL) at the 24th week>

The variation such as table 26 of the Apo B of subject is presented compared with baseline when visiting (the 24th week) at the 6th time.

Every group of Apo B baseline is similar: 121.90 ± 20.57mg/dL of gigue column spit of fland/rosuvastatin FDC group, gigue Arrange 128.40 ± 23.65mg/dL of spit of fland group and 119.46 ± 22.15mg/dL of rosuvastatin group.Visited at the 6th time (the 24 weeks) when, all 3 groups all show that Apo B is significantly reduced compared with baseline.

The LS average value of Apo B when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), wherein the LS average value passes through the analysis of covariance of the Apo B baseline as covariant (ANCOVA) it obtaining, gigue column spit of fland/rosuvastatin FDC group shows that Apo B is significantly reduced compared with the group of gigue column spit of fland, and with Rosuvastatin group is not significantly different compared to variable quantity.

[table 26]

<variation of lipoprotein (a) (mg/dL) at the 24th week>

When visiting (the 24th week) at the 6th time compared with baseline the variation of the lipoprotein (a) (Lp (a)) of subject such as 27 institute of table It presents.

Every group of Lp (a) baseline is similar: 17.27 ± 19.72mg/dL of gigue column spit of fland/rosuvastatin FDC group, gigue Arrange 19.41 ± 19.31mg/dL of spit of fland group and 16.12 ± 14.06mg/dL of rosuvastatin group.The (the 24th is visited at the 6th time Week) when, gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group show that Lp (a) is dramatically increased compared with baseline, and Gigue column spit of fland group shows that Lp (a) does not have significant changes compared with baseline.

The LS average value of Lp (a) when comparing the 6th time and visiting (the 24th week) between described group relative to the variation of baseline When (least square average value), wherein the LS average value passes through the analysis of covariance of Lp (a) baseline as covariant (ANCOVA) it obtaining, gigue column spit of fland/rosuvastatin FDC group shows that Lp (a) is dramatically increased compared with the group of gigue column spit of fland, and with Rosuvastatin group is not significantly different compared to variable quantity.

[table 27]

<variation of Apo A-I/Apo B ratio at the 24th week>

When visiting (the 24th week) at the 6th time and baseline compares the Apo A-I/Apo B ratio for the subject for including in FAS Variation such as table 28 is presented.

Every group of Apo A-I/Apo B ratio baseline is similar: gigue column spit of fland/rosuvastatin FDC group 0.87 ± 0.25, The 0.86 ± 0.21 of 0.91 ± 0.23 and rosuvastatin group of gigue column spit of fland group.When visiting (the 24th week) at the 6th time, gigue Column spit of fland/rosuvastatin FDC group and rosuvastatin group show that Apo A-I/Apo B ratio significantly reduces compared with baseline, and And gigue column spit of fland group shows that Apo A-I/Apo B ratio does not have significant changes compared with baseline.

Change of the Apo A-I/Apo B ratio relative to baseline when comparing the 6th time and visiting (the 24th week) between described group When LS average value (the least square average value) of change, wherein the LS average value passes through Apo A-I/Apo B ratio baseline conduct The analysis of covariance (ANCOVA) of covariant obtains, and gigue column spit of fland/rosuvastatin FDC group is shown compared with the group of gigue column spit of fland Apo A-I/Apo B ratio significantly reduces, and variable quantity is not significantly different compared with rosuvastatin group.

[table 28]

(3) efficacy assessments result is summarized

For HbA1c, compare gigue column spit of fland/rosuvastatin FDC group and rosuvastatin group variable quantity.For LDL- C compares the change rate of gigue column spit of fland/rosuvastatin FDC group and gigue column spit of fland group.By comparing every time, it was confirmed that gigue column Spit of fland/rosuvastatin FDC group superiority.

When visiting (the 24th week) at the 6th time, compared with baseline, the least square average value of HbA1c variation are as follows: gigue column The 0.273 ± 0.080% of spit of fland/rosuvastatin FDC group -0.539 ± 0.081% and rosuvastatin group.It is less than from the upper limit 0 95%CI (- 1.035, -0.588), it was confirmed that compared with rosuvastatin group, gigue column spit of fland/rosuvastatin FDC group exists Superiority in terms of the effect of reducing HbA1c.

When visiting (the 24th week) at the 6th time, compared with baseline, the least square average value of LDL-C change rate (%) are as follows: - 1.135 ± the 1.939% of gigue column spit of fland/rosuvastatin FDC group -53.002 ± 1.929% and gigue column spit of fland group.From upper Limit the 95%CI (- 57.271, -46.463) less than 0, it was confirmed that compared with the group of gigue column spit of fland, gigue column spit of fland/rosuvastatin Superiority of the FDC group in terms of the effect of reducing LDL-C.

Secondly, the variation for gigue column spit of fland/rosuvastatin FDC group HbA1c and LDL-C, HbA1c and gigue are arranged Spit of fland group compares, and by LDL-C compared with rosuvastatin group.

When visiting (the 24th week) at the 6th time, compared with baseline, the least square average value of HbA1c variable quantity are as follows: gigue Arrange -1.007 ± the 0.080% of spit of fland/gigue column spit of fland FDC group -0.539 ± 0.081% and gigue column spit of fland group.Two groups are all aobvious Show the significant decrease (P < 0.0001) compared with baseline, but gigue column spit of fland/rosuvastatin FDC group is shown compared with the group of gigue column spit of fland Smaller HbA1c is reduced, and there are statistically-significant difference (P=0.0001).

When visiting (the 24th week) at the 6th time, compared with baseline, the least square average value of LDL-C change rate (%) are as follows: - 53.89 ± the 16.64% of gigue column spit of fland/rosuvastatin FDC group -52.57 ± 20.56% and rosuvastatin group.Two A group of all display significantly reduces (P < 0.0001) compared with baseline, and the LDL-C change rate of two groups is not significantly different (P =0.6354).

During 24 weeks every time when visiting, gigue column spit of fland/rosuvastatin FDC group is shown compared with rosuvastatin group HbA1c and FPG is significantly reduced, and LDL-C is significantly reduced compared with the group of gigue column spit of fland.

During 24 weeks, when visiting every time, gigue column spit of fland/rosuvastatin FDC group HbA1c is shown compared with baseline Writing reduces.When the 4th visits (the 8th week), HbA1c relative to the variation of baseline least square average value -0.686 ± 0.055% is maximum reduction.On the other hand, in rosuvastatin group, HbA1c is slightly reduced when the 4th visits (the 8th week) Extremely -0.074 ± 0.055%, but then increase again.Every time visit when, gigue column spit of fland/rosuvastatin FDC group show and Rosuvastatin group compared to HbA1c significantly reduce, and between group variable quantity difference at the 24th week maximum (- 0.812 ± 0.113% (P < 0.0001)).Meanwhile when compared with the group of gigue column spit of fland, the gigue column spit of fland after the 5th visits (the 16th week) Group display significant bigger HbA1c compared with gigue column spit of fland/rosuvastatin FDC group is reduced.

During 24 weeks, when visiting every time, gigue column spit of fland/rosuvastatin FDC group FPG is significant compared with baseline It reduces.When the 4th visits (the 8th week), FPG relative to the variation of baseline least square average value -11.962 ± 2.801mg/dL being maximum reduction.On the other hand, in rosuvastatin group, FPG is continuously increased.When visiting every time, gigue Column spit of fland/rosuvastatin FDC group shows compared with rosuvastatin group FPG significant decrease, and variable quantity between group at the 24th week Difference be -20.627 ± 4.417mg/dL.Meanwhile when compared with the group of gigue column spit of fland, the gigue column spit of fland group when visiting every time Show that significant bigger FPG is reduced compared with gigue column spit of fland/rosuvastatin FDC group.

During 24 weeks, when visiting every time, gigue column spit of fland/rosuvastatin FDC group LDL-C is shown compared with baseline Writing reduces.When visiting (the 24th week) at the 6th time, LDL-C relative to the variation of baseline least square average value -53.002 ± 1.929% is maximum reduction.On the other hand, in the group of gigue column spit of fland, LDL-C does not have significant changes relative to baseline.Each When visiting, gigue column spit of fland/rosuvastatin FDC group shows that compared with the group of gigue column spit of fland, LDL-C is significantly reduced, and at the 24th week The difference of change rate is -51.867 ± 2.745% between group.It is lucky when visiting every time meanwhile when compared with rosuvastatin group The reduction of LDL-C does not vary significantly from rosuvastatin group in Ge Lieting/rosuvastatin FDC group.

As other evaluation parameters of diabetes index, when visiting (the 24th week) at the 6th time, gigue column spit of fland/rosuvastatin Spit of fland FDC group shows that HOMA- β and HOMA-IR are significantly improved.

When visiting (the 24th week) at the 6th time, gigue column spit of fland/rosuvastatin FDC group is shown and baseline or each control group phase There is no significant changes than Diagnostic Value of Fasting Serum proinsulin/insulin ratio.

When visiting (the 24th week) at the 6th time, gigue column spit of fland/rosuvastatin FDC group shows the Diagnostic Value of Fasting Serum compared with baseline C- peptide does not have significant changes, and variable quantity is not significantly different compared with rosuvastatin group, but shows and gigue column spit of fland group phase Increase (P=0.0488) more statistically significant than Diagnostic Value of Fasting Serum C- peptide.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, HOMA- β The least square average value of variation is 11.249 ± 2.832, the value of the least square average value and rosuvastatin group (0.531 ± 3.005) it compares and dramatically increases (P=0.0100), and value (15.279 ± 2.892) phase with gigue column spit of fland group Than being not significantly different.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, HOMA- The least square average value of IR variation is -0.092 ± 0.245, the least square average value no significant changes compared with baseline, Compared with the value (0.670 ± 0.258) of rosuvastatin group significantly reduce (P=0.0331), and with gigue column spit of fland group The value (- 0.382 ± 0.250) is compared and is not significantly different.

Gigue column spit of fland/rosuvastatin FDC group most of evaluation parameters relevant to dyslipidemia are visited at the 6th time It is significantly improved when (the 24th week).

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, Apo B The least square average value of variable quantity is -56.393 ± 1.903mg/dL, which significantly reduces compared with baseline.Gigue column spit of fland/ Rosuvastatin FDC group shows the significant decrease (P < 0.0001) compared with gigue column spit of fland group (- 4.456 ± 1.961), and and sieve Rosuvastatin group (- 56.118 ± 2.028) is compared and is not significantly different.These results are consistent with the trend of LDL-C.

During 24 weeks, when visiting every time, gigue column spit of fland/rosuvastatin FDC group total cholesterol (TC) and baseline Compared to significant decrease.When visiting (the 24th week) at the 6th time, TC relative to the variation of baseline least square average value 78.175 ± 2.761mg/dL being maximum reduction.When visiting every time, gigue column spit of fland/rosuvastatin FDC group is shown and gigue column spit of fland group phase It is reduced than significantly bigger TC, and the difference of variable quantity is -75.024 ± 3.935mg/dL between group at the 24th week.Meanwhile When compared with rosuvastatin group, gigue column spit of fland/rosuvastatin FDC group shows that each TC when visiting reduces no significance difference It is different.

During 24 weeks, when visiting every time, gigue column spit of fland/rosuvastatin FDC group triglycerides (TG) and baseline Compared to significant decrease.When visiting (the 24th week) at the 6th time, least square average value -62.433 of the TG relative to the variation of baseline ± 8.771mg/dL is maximum reduction.When visiting every time, gigue column spit of fland/rosuvastatin FDC group is shown and gigue column spit of fland group It is reduced compared to significantly bigger TG, and the difference of variable quantity is -55.440 ± 12.391mg/dL between group at the 24th week.Meanwhile When compared with rosuvastatin group, it is not significant that gigue column spit of fland/rosuvastatin FDC group shows that TG when visiting every time is reduced Difference.

During 24 weeks, every time visit when, gigue column spit of fland/rosuvastatin FDC group LDL-C/HDL-C ratio and Baseline is compared to significant decrease.When visiting (the 24th week) at the 6th time, minimum of the LDL-C/HDL-C ratio relative to the variation of baseline Two to multiply average value -1.649 ± 0.059 be maximum reduction.Every time visit when, gigue column spit of fland/rosuvastatin FDC group show and Gigue column spit of fland group is reduced compared to significant bigger LDL-C/HDL-C ratio, and at the 24th week between group the difference of variable quantity be- 1.637±0.084.Meanwhile when compared with rosuvastatin group, gigue column spit of fland/rosuvastatin FDC group shows and visits every time When LDL-C/HDL-C ratio reduction be not significantly different.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, Apo A- The least square average value of I/Apo B rate of change amount is -0.409 ± 0.015, which significantly reduces compared with baseline.Gigue Column spit of fland/rosuvastatin FDC group shows the significant decrease (P < 0.0001) compared with gigue column spit of fland group (- 0.014 ± 0.016), and And it is not significantly different compared with rosuvastatin group (- 0.425 ± 0.016).These results and LDL-C/HDL-C ratio become Gesture is consistent.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, HDL-C The least square average value of variation is 1.452 ± 0.804mg/dL, the value no significant changes compared with baseline.Gigue column spit of fland/ Rosuvastatin FDC group is shown compared with gigue column spit of fland group (- 0.594 ± 0.804mg/dL) to be cut down without significant difference, but with Luo Su Statin group (4.535 ± 0.796mg/dL) compares significant smaller increase.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, Apo A- The least square average value of I variation is 0.996 ± 2.092mg/dL, the value no significant changes compared with baseline.Gigue column spit of fland/ Rosuvastatin FDC group show with gigue column spit of fland group (- 2.909 ± 2.141mg/dL) or rosuvastatin group (6.755 ± 2.221mg/dL) compared to being not significantly different.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, lipoprotein (a) the least square average value changed is 5.930 ± 1.160mg/dL, which dramatically increases compared with baseline.Gigue column spit of fland/sieve Rosuvastatin FDC group shows and dramatically increases compared with gigue column spit of fland group (- 0.435 ± 1.188mg/dL), but and rosuvastatin Group (4.800 ± 1.232mg/dL) is compared and is not significantly different.

Meanwhile when visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, waistline and weight do not have Great changes have taken place.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, waistline becomes The least square average value of change is -0.738 ± 0.373cm, which significantly reduces compared with baseline.Gigue column spit of fland/rosuvastatin Spit of fland FDC group is shown compared with gigue column spit of fland group (- 0.144 ± 0.372cm) or rosuvastatin group (- 0.150 ± 0.369cm) not There were significant differences.

When visiting (the 24th week) at the 6th time, in gigue column spit of fland/rosuvastatin FDC group, compared with baseline, weight becomes The least square average value of change is -0.132 ± 0.244kg, the value no significant changes compared with baseline.Gigue column spit of fland/Luo Su It cuts down statin FDC group and shows and be not significantly different compared with gigue column spit of fland group (- 0.407 ± 0.0.243kg), but and rosuvastatin Group (- 0.893 ± 0.241kg) compares significant smaller reduction.

Claims (16)

1. a kind of combination preparation, the combination preparation include as the gigue column spit of fland of inhibitors of dipeptidyl IV or its pharmaceutically Acceptable salt and as the rosuvastatin of HMG-CoA reductase inhibitor or its pharmaceutically acceptable salt as activity at Point.

2. the combination preparation of claim 1, the combination preparation is the dosage form of fixed dosage combination.

3. the combination preparation of claim 1, the combination preparation is the dosage form of bilayer tablet, and the bilayer tablet includes comprising Ji The layer of Ge Lieting or its pharmaceutically acceptable salt and layer comprising rosuvastatin or its pharmaceutically acceptable salt.

4. the combination preparation of claim 1, wherein the pharmaceutically acceptable salt in gigue column spit of fland is tartrate.

5. the combination preparation of claim 1, wherein the pharmaceutically acceptable salt of rosuvastatin is calcium salt.

6. the combination preparation of claim 2, the combination preparation also includes pharmaceutically acceptable excipient.

7. the combination preparation of claim 6, wherein the pharmaceutically acceptable excipient is calcium phosphate dibasic dihydrate.

8. the combination preparation of claim 3, the combination preparation also includes pharmaceutically acceptable excipient.

9. the combination preparation of claim 8, wherein including in the layer comprising gigue column spit of fland or its pharmaceutically acceptable salt Pharmaceutically acceptable excipient be sodium stearyl fumarate.

10. the combination preparation of claim 8, wherein being wrapped in the layer comprising rosuvastatin or its pharmaceutically acceptable salt The pharmaceutically acceptable excipient contained is calcium phosphate dibasic dihydrate.

11. the combination preparation of claim 1, the combination preparation includes 25mg to the gigue column spit of fland 100mg or pharmaceutically acceptable Salt.

12. the combination preparation of claim 1, the combination preparation include 1mg to 50mg rosuvastatin or its can pharmaceutically connect The salt received.

13. the combination preparation of Claims 2 or 3, the combination preparation includes 50mg gigue column spit of fland or pharmaceutically acceptable salt With 5mg rosuvastatin or its pharmaceutically acceptable salt.

14. the combination preparation of Claims 2 or 3, the combination preparation includes 50mg gigue column spit of fland or pharmaceutically acceptable salt With 10mg rosuvastatin or its pharmaceutically acceptable salt.

15. the combination preparation of Claims 2 or 3, the combination preparation includes 50mg gigue column spit of fland or pharmaceutically acceptable salt With 20mg rosuvastatin or its pharmaceutically acceptable salt.

16. the combination preparation of Claims 2 or 3, the combination preparation includes 50mg gigue column spit of fland or pharmaceutically acceptable salt With 40mg rosuvastatin or its pharmaceutically acceptable salt.